{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:03:19Z","timestamp":1791478999634,"version":"4.3.4"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Vaccines have been pivotal in reducing the incidence and severity of infectious diseases, improving population health, and lowering mortality rates globally. While substantial progress has been made in optimizing vaccine formulations, adjuvants, and schedules, comparatively less attention has been given to how the site of vaccination may influence immunologic outcomes. This review examines the impact of the administration of prime and booster vaccine doses in the same (ipsilateral) versus the opposite arms (contralateral) on vaccine immunogenicity. We review animal model and human studies evaluating the impact of ipsilateral versus contralateral COVID-19 and non-COVID-19 vaccine boosting on immunologic outcomes with a focus on the germinal center response, antibody production, and T cell activation. While some studies suggest that ipsilateral administration may enhance the quality of germinal center B cell responses and antibody magnitude, data across different studies have been inconsistent. Relatively few studies have compared ipsilateral versus contralateral boosting, and differences in study design and outcomes have limited the ability to draw conclusions as to whether one is superior to the other. This review highlights a noteworthy and underexplored area in vaccinology and the need for future research to clarify whether ipsilateral\/contralateral boosting strategies matter. To answer this question, high-quality, randomized controlled trials evaluating different types of vaccines that consider immunologic mechanisms, capture key time points and appropriate specimens, and evaluate early and long-term immunogenicity endpoints are required.<\/jats:p>","DOI":"10.3390\/vaccines13121225","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T13:53:30Z","timestamp":1764856410000},"page":"1225","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Review of the Effects of Ipsilateral or Contralateral Vaccine Boosting on the Adaptive Immune Response"],"prefix":"10.3390","volume":"13","author":[{"given":"Amal","family":"Naji","sequence":"first","affiliation":[{"name":"Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0489-0074","authenticated-orcid":false,"given":"Hana M.","family":"El Sahly","sequence":"additional","affiliation":[{"name":"Departments of Molecular Virology and Microbiology and Medicine, Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7727-6086","authenticated-orcid":false,"given":"Jennifer A.","family":"Whitaker","sequence":"additional","affiliation":[{"name":"Departments of Molecular Virology and Microbiology and Medicine, Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Greenwood, B. (2014). The contribution of vaccination to global health: Past, present and future. Philos. Trans. R. Soc. Lond. B Biol. Sci., 369.","DOI":"10.1098\/rstb.2013.0433"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12313","DOI":"10.1073\/pnas.1400475111","article-title":"Valuing vaccination","volume":"111","author":"Bloom","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Rodrigues, C.M.C., and Plotkin, S.A. (2020). Impact of Vaccines; Health, Economic and Social Perspectives. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.01526"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41577-020-00479-7","article-title":"A guide to vaccinology: From basic principles to new developments","volume":"21","author":"Pollard","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"den Boon, S., Ahmed, S., and Sarker, A.R. (2023). Economic evaluations of immunization programs as an indispensable tool for policymakers. BMC Health Serv. Res., 23.","DOI":"10.1186\/s12913-023-10071-z"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Peng, M. (2020). Outbreak of COVID-19: An emerging global pandemic threat. Biomed. Pharmacother., 129.","DOI":"10.1016\/j.biopha.2020.110499"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106054","DOI":"10.1016\/j.ijantimicag.2020.106054","article-title":"Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): A global pandemic and treatment strategies","volume":"56","author":"Sharma","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41577-021-00554-7","article-title":"Modulation of immune responses to vaccination by the microbiota: Implications and potential mechanisms","volume":"22","author":"Lynn","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e00084-18","DOI":"10.1128\/CMR.00084-18","article-title":"Factors That Influence the Immune Response to Vaccination","volume":"32","author":"Zimmermann","year":"2019","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1002\/jmv.27485","article-title":"Host factors and vaccine efficacy: Implications for COVID-19 vaccines","volume":"94","author":"Falahi","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lau, C.S., and Aw, T.C. (2022). Considerations in Understanding Vaccine Effectiveness. Vaccines, 11.","DOI":"10.3390\/vaccines11010020"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1136\/bmjebm-2021-111901","article-title":"Factors influencing estimated effectiveness of COVID-19 vaccines in non-randomised studies","volume":"27","author":"Ioannidis","year":"2022","journal-title":"BMJ Evid. Based Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/ni.2039","article-title":"Immunological mechanisms of vaccination","volume":"12","author":"Pulendran","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.cell.2020.09.040","article-title":"Why and How Vaccines Work","volume":"183","author":"Iwasaki","year":"2020","journal-title":"Cell"},{"key":"ref_15","first-page":"20","article-title":"Vaccines--How and why they work","volume":"22","author":"Casey","year":"2016","journal-title":"Nurs. N. Z."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1016\/S0140-6736(21)02388-6","article-title":"Boosters appear effective, but are they always needed?","volume":"398","author":"Reddy","year":"2021","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ziegler, L., Klemis, V., Schmidt, T., Schneitler, S., Baum, C., Neumann, J., Becker, S.L., G\u00e4rtner, B.C., Sester, U., and Sester, M. (2023). Differences in SARS-CoV-2 specific humoral and cellular immune responses after contralateral and ipsilateral COVID-19 vaccination. eBioMedicine, 95.","DOI":"10.1016\/j.ebiom.2023.104743"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Pettini, E., Medaglini, D., and Ciabattini, A. (2022). Profiling the B cell immune response elicited by vaccination against the respiratory virus SARS-CoV-2. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1058748"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41423-023-01095-w","article-title":"B-cell and antibody responses to SARS-CoV-2: Infection, vaccination, and hybrid immunity","volume":"21","author":"Lapuente","year":"2024","journal-title":"Cell Mol. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.cell.2022.01.027","article-title":"Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals","volume":"185","author":"Lederer","year":"2022","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41586-021-03738-2","article-title":"SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses","volume":"596","author":"Turner","year":"2021","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chen, M., Venturi, V., and Munier, C.M.L. (2023). Dissecting the Protective Effect of CD8(+) T Cells in Response to SARS-CoV-2 mRNA Vaccination and the Potential Link with Lymph Node CD8(+) T Cells. Biology, 12.","DOI":"10.3390\/biology12071035"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2287118","DOI":"10.1080\/22221751.2023.2287118","article-title":"The characterization of CD8(+) T-cell responses in COVID-19","volume":"13","author":"Yang","year":"2024","journal-title":"Emerg. Microbes Infect."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4631","DOI":"10.1038\/s41467-022-32324-x","article-title":"COVID-19 mRNA booster vaccine induces transient CD8+ T effector cell responses while conserving the memory pool for subsequent reactivation","volume":"13","author":"Reinscheid","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.immuni.2016.09.001","article-title":"Germinal Center B Cell Dynamics","volume":"45","author":"Mesin","year":"2016","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zimmermann, P., Ritz, N., Perrett, K.P., Messina, N.L., van der Klis, F.R.M., and Curtis, N. (2021). Correlation of Vaccine Responses. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.646677"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.cell.2022.01.018","article-title":"Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination","volume":"185","author":"Nielsen","year":"2022","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.medj.2020.12.006","article-title":"A booster dose enhances immunogenicity of the COVID-19 vaccine candidate ChAdOx1 nCoV-19 in aged mice","volume":"2","author":"Foster","year":"2021","journal-title":"Med"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e0057424","DOI":"10.1128\/jvi.00574-24","article-title":"Ipsilateral or contralateral boosting of mice with mRNA vaccines confers equivalent immunity and protection against a SARS-CoV-2 Omicron strain","volume":"98","author":"Ying","year":"2024","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"113665","DOI":"10.1016\/j.celrep.2023.113665","article-title":"Ipsilateral immunization after a prior SARS-CoV-2 mRNA vaccination elicits superior B cell responses compared to contralateral immunization","volume":"43","author":"Jiang","year":"2024","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1084\/jem.130.2.287","article-title":"The proliferative and anamnestic antibody response of rabbit lymphoid cells in vitro. I. Immunological memory in the lymph nodes draining and contralateral to the site of a primary antigen injection","volume":"130","author":"Jacobson","year":"1969","journal-title":"J. Exp. Med."},{"key":"ref_32","first-page":"17","article-title":"PRE-EXPOSURE RABIES PROPHYLAXIS PROBLEMS AND PROCEDURES","volume":"33","author":"Peck","year":"1964","journal-title":"Ind. Med. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/S1473-3099(14)71057-6","article-title":"Immunological effect of administration of sequential doses of Haemophilus influenzae type b and pneumococcal conjugate vaccines in the same versus alternating limbs in the routine infant immunisation schedule: An open-label randomised controlled trial","volume":"15","author":"Iro","year":"2015","journal-title":"Lancet Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"eabn5311","DOI":"10.1126\/sciimmunol.abn5311","article-title":"Recall of B cell memory depends on relative locations of prime and boost immunization","volume":"7","author":"Kuraoka","year":"2022","journal-title":"Sci. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e176411","DOI":"10.1172\/JCI176411","article-title":"Contralateral second dose improves antibody responses to a 2-dose mRNA vaccination regimen","volume":"134","author":"Fazli","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pattinson, D., Jester, P., Gu, C., Guan, L., Armbrust, T., Petrie, J.G., King, J.P., Nguyen, H.Q., Belongia, E.A., and Halfmann, P. (2024). Ipsilateral and contralateral coadministration of influenza and COVID-19 vaccines produce similar antibody responses. eBioMedicine, 103.","DOI":"10.1016\/j.ebiom.2024.105103"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"540.e1","DOI":"10.1016\/j.cmi.2022.11.009","article-title":"Effect of same-arm versus cross-arm administration of sequential doses of BNT162b2 on short-term vaccine effectiveness-a retrospective cohort study","volume":"29","author":"Grupel","year":"2023","journal-title":"Clin. Microbiol. Infect."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/12\/1225\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T14:16:26Z","timestamp":1764857786000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/12\/1225"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,4]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["vaccines13121225"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13121225","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,4]]}}}