#18,459
Despite the daunting title, and its highly detailed and formidable narrative, the question posed by a study published this week in Cell is fairly simple; is there an advantage to getting both the prime and booster pandemic vaccine in the same arm?
Previous studies have suggested that it probably doesn't matter, or even that alternating arms produces a superior immune response (see JCI Contralateral second dose improves antibody responses to a 2-dose mRNA vaccination regimen).
While this JCI study published in the spring of 2024 (see Switching arms improves effectiveness of two-dose vaccinations, OHSU study suggests) seemed to have answered the question, since then new research has emerged suggesting just the opposite.
Note: Methods, materials, and endpoints can differ widely between studies, making it possible for two or more valid studies to come to different conclusions. The devil is always in the details.
First, a study published last March in the Journal of Immunology:
Modulation of germinal center and antibody dynamics via ipsilateral versus contralateral immunization against SARS-CoV-2
Lauren Burmas , Wen Shi Lee , Andrew Kelly , Rosela Webster , Robyn Esterbauer , Stephen J Kent , Adam K Wheatley , Jennifer A Juno , Hyon-Xhi TanFrom the press release:
The Journal of Immunology, Volume 214, Issue 3, March 2025, Pages 335–346, https://doi.org/10.1093/jimmun/vkae067 Published: 09 March 2025
Multi-dose vaccines administered in the same site boost immune response
New research suggests that receiving multiple doses of a vaccine in the same limb leads to faster antibody development, an important strategy for providing immunity as quickly as possible during a pandemic or disease outbreak.
The study, published in The Journal of Immunology, found that mice that received both doses of the COVID-19 vaccine in the same limb (ipsilateral) had a faster initial antibody response in the weeks after vaccination compared to those whose vaccines were administered in different limbs (contralateral). In the long term, both vaccination approaches resulted in similar antibody development or immunity levels.
Granted, laboratory animal studies have limitations ( it's been commonly said that `Mice lie and monkeys exaggerate'), but these human proxies are often the only ethical or practical choice for biomedical research
Today, however, we have a new study that utilizes both lab-animal and human results, which points towards ipsilateral vaccination as producing a superior B cell memory response. While both methods achieve similar long-term immunity, getting both vaccines in the same arm led to a more rapid immune response.
Macrophages direct location-dependent recall of B cell memory to vaccination
Rama Dhenni1,2,12 ∙ Alexandra Carey Hoppé3,12 ∙ Arnold Reynaldi4 ∙ … ∙ Vanessa Venturi3,13 vventuri@kirby.unsw.edu.au ∙ C. Mee Ling Munier3,13 cmunier@kirby.unsw.edu.au ∙ Tri Giang Phan1,2,13,14 t.phan@garvan.org.au
Received September 19, 2023; Revised August 31, 2024; Accepted April 2, 2025; Published online April 28, 2025
DOI: 10.1016/j.cell.2025.04.005 External Link
Copyright: © 2025 The Author(s). Published by Elsevier Inc.Highlights
• Memory B cells in the draining lymph node (dLN) re-enter germinal centers 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 centers (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 harbor 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.
This is, as previously noted, and extremely detailed and highly technical report - which while undoubtably a delight for virologists - may be a bit much for many to wade through. In its stead we have the following press release from the Garvan Institute for Medical Research in NSW, Australia.
28 Apr 2025
Left or right arm? New research reveals why vaccination site matters for immune response
Scientists have uncovered why vaccines can elicit a stronger immune response if they are administered in the same arm.
Dr Rama Dhenni and Professor Tri PhanDr Rama Dhenni and Professor Tri Phan
Sydney scientists have revealed why receiving a booster vaccine in the same arm as your first dose can generate a more effective immune response more quickly. The study, led by the Garvan Institute of Medical Research and the Kirby Institute at UNSW Sydney and published in the journal Cell, offers new insight that could help improve future vaccination strategies.
The researchers found that when a vaccine is administered, specialised immune cells called macrophages became ‘primed’ inside lymph nodes. These macrophages then direct the positioning of memory B cells to more effectively respond to the booster when given in the same arm.
The findings, made in mice and validated in human participants, 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 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.”
While this may not be the last word on the topic, during the opening months of a pandemic - when vaccines may be both scarce and potentially less effective - any advantage is probably worth pursuing.
This study reminds us that our understanding of the human immune system continues to evolve, and that it is far more complex than we know.
