Poole, J. & Holladay, A. J. Thucydides and the Plague of Athens. Classical Q. 29, 282–300 (1979).
Jenner E. In Scientific and Medical Knowledge Production, 1796–1918. 40–50 (Routledge, 2023).
Palin, A. C. et al. The persistence of memory: defining, engineering, and measuring vaccine durability. Nat. Immunol. 23, 1665–1668 (2022).
Pooley, N. et al. Durability of vaccine-induced and natural immunity against COVID-19: a narrative review. Infect. Dis. Ther. 12, 367–387 (2023).
Combadiere, B., Siberil, S. & Duffy, D. Keeping the memory of influenza viruses. Pathol. Biol. 58, e79–e86 (2010).
Puissant, B. & Combadiere, B. Keeping the memory of smallpox virus. Cell Mol. Life Sci. 63, 2249–2259 (2006).
Amanna, I. J., Carlson, N. E. & Slifka, M. K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007).
Vashishtha, V. M. & Kumar, P. The durability of vaccine-induced protection: an overview. Expert Rev. Vaccines 23, 389–408 (2024).
Menegale, F. et al. Evaluation of waning of SARS-CoV-2 vaccine-induced immunity: a systematic review and meta-analysis. JAMA Netw. Open 6, e2310650 (2023).
Feikin, D. R. et al. Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: results of a systematic review and meta-regression. Lancet 399, 924–944 (2022).
Sette, A. & Crotty, S. Immunological memory to SARS-CoV-2 infection and COVID-19 vaccines. Immunol. Rev. 310, 27–46 (2022).
Akkaya, M., Kwak, K. & Pierce, S. K. B cell memory: building two walls of protection against pathogens. Nat. Rev. Immunol. 20, 229–238 (2020).
Inoue, T. & Kurosaki, T. Memory B cells. Nat. Rev. Immunol. 24, 5–17 (2024).
Kunzli, M. & Masopust, D. CD4(+) T cell memory. Nat. Immunol. 24, 903–914 (2023).
Pollard, A. J. & Bijker, E. M. A guide to vaccinology: from basic principles to new developments. Nat. Rev. Immunol. 21, 83–100 (2021).
Phan, T. G., Gray, E. E. & Cyster, J. G. The microanatomy of B cell activation. Curr. Opin. Immunol. 21, 258–265 (2009).
Garside, P. et al. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96–99 (1998).
Crotty, S. T follicular helper cell biology: a decade of discovery and diseases. Immunity 50, 1132–1148 (2019).
Toyama, H. et al. Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells. Immunity 17, 329–339 (2002).
Taylor, J. J., Pape, K. A. & Jenkins, M. K. A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J. Exp. Med. 209, 597–606 (2012).
Akkaya, M. & Pierce, S. K. From zero to sixty and back to zero again: the metabolic life of B cells. Curr. Opin. Immunol. 57, 1–7 (2019).
Elgueta, R. et al. CCR6-dependent positioning of memory B cells is essential for their ability to mount a recall response to antigen. J. Immunol. 194, 505–513 (2015).
Kim, S. T. et al. Human extrafollicular CD4(+) Th cells help memory B cells produce Igs. J. Immunol. 201, 1359–1372 (2018).
Joo, H. M., He, Y. & Sangster, M. Y. Broad dispersion and lung localization of virus-specific memory B cells induced by influenza pneumonia. Proc. Natl Acad. Sci. USA 105, 3485–3490 (2008).
Bortnick, A. & Allman, D. What is and what should always have been: long-lived plasma cells induced by T cell-independent antigens. J. Immunol. 190, 5913–5918 (2013).
Manz, R. A., Lohning, M., Cassese, G., Thiel, A. & Radbruch, A. Survival of long-lived plasma cells is independent of antigen. Int Immunol. 10, 1703–1711 (1998).
Inoue, T., Moran, I., Shinnakasu, R., Phan, T. G. & Kurosaki, T. Generation of memory B cells and their reactivation. Immunol. Rev. 283, 138–149 (2018).
Purtha, W. E., Tedder, T. F., Johnson, S., Bhattacharya, D. & Diamond, M. S. Memory B cells, but not long-lived plasma cells, possess antigen specificities for viral escape mutants. J. Exp. Med. 208, 2599–2606 (2011).
Jozwik, A. et al. RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection. Nat. Commun. 6, 10224 (2015).
Wilkinson, T. M. et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat. Med. 18, 274–280 (2012).
Sridhar, S. et al. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat. Med. 19, 1305–1312 (2013).
Kervevan, J. & Chakrabarti, L. A. Role of CD4+ T cells in the control of viral infections: recent advances and open questions. Int. J. Mol. Sci. 22, 523 (2021).
Swain, S. L., McKinstry, K. K. & Strutt, T. M. Expanding roles for CD4(+) T cells in immunity to viruses. Nat. Rev. Immunol. 12, 136–148 (2012).
Di Rosa, F. & Gebhardt, T. Bone marrow T cells and the integrated functions of recirculating and tissue-resident memory T cells. Front Immunol. 7, 51 (2016).
Humphries, D. C. et al. Pulmonary-resident memory lymphocytes: pivotal orchestrators of local immunity against respiratory infections. Front Immunol. 12, 738955 (2021).
Siracusa, F. et al. Nonfollicular reactivation of bone marrow resident memory CD4 T cells in immune clusters of the bone marrow. Proc. Natl Acad. Sci. USA 115, 1334–1339 (2018).
Verdon, D. J., Mulazzani, M. & Jenkins, M. R. Cellular and molecular mechanisms of CD8(+) T cell differentiation, dysfunction and exhaustion. Int. J. Mol. Sci. 21, 7357 (2020).
Joshi, N. S. & Kaech, S. M. Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. J. Immunol. 180, 1309–1315 (2008).
Schiller, J. T., Castellsague, X. & Garland, S. M. A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine 30, F123–F138 (2012).
Schiller, J. & Lowy, D. Explanations for the high potency of HPV prophylactic vaccines. Vaccine 36, 4768–4773 (2018).
Griffin, D. E. Measles vaccine. Viral Immunol. 31, 86–95 (2018).
Gans, H. A. et al. Measles humoral and cell-mediated immunity in children aged 5–10 years after primary measles immunization administered at 6 or 9 months of age. J. Infect. Dis. 207, 574–582 (2013).
Lin, W. H., Pan, C. H., Adams, R. J., Laube, B. L. & Griffin, D. E. Vaccine-induced measles virus-specific T cells do not prevent infection or disease but facilitate subsequent clearance of viral RNA. mBio 5, e01047 (2014).
Plotkin, S. A. Correlates of protection induced by vaccination. Clin. Vaccin. Immunol. 17, 1055–1065 (2010).
Walls, A. C. et al. Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2. Cell 183, 1367–82.e17 (2020).
Kato, Y. et al. Multifaceted effects of antigen valency on B cell response composition and differentiation in vivo. Immunity 53, 548–63.e8 (2020).
Mateus, J. et al. Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells. Science 374, eabj9853 (2021).
Billeskov, R., Beikzadeh, B. & Berzofsky, J. A. The effect of antigen dose on T cell-targeting vaccine outcome. Hum. Vaccin Immunother. 15, 407–411 (2019).
Bhattacharya, D. Instructing durable humoral immunity for COVID-19 and other vaccinable diseases. Immunity 55, 945–964 (2022).
Li, C. et al. Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine. Nat. Immunol. 23, 543–555 (2022).
Hou, Y. et al. Advanced subunit vaccine delivery technologies: from vaccine cascade obstacles to design strategies. Acta Pharm. Sin. B 13, 3321–3338 (2023).
Heidary, M. et al. A comprehensive review of the protein subunit vaccines against COVID-19. Front. Microbiol. 13, 927306 (2022).
Didierlaurent, A. M. et al. AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J. Immunol. 183, 6186–6197 (2009).
Pedersen, G. K., Worzner, K., Andersen, P. & Christensen, D. Vaccine adjuvants differentially affect kinetics of antibody and germinal center responses. Front Immunol. 11, 579761 (2020).
Wohner, M. & Nimmerjahn, F. Cytotoxic IgG: mechanisms, functions, and applications. Immunity 58, 1378–1395 (2025).
Lasrado, N. et al. Waning immunity and IgG4 responses following bivalent mRNA boosting. Sci. Adv. 10, eadj9945 (2024).
Kalkeri, R. et al. Anti-spike IgG4 and Fc effector responses: the impact of SARS-CoV-2 vaccine platform-specific priming and immune imprinting. J. Infect. 91, 106543 (2025).
Martinez, D. R. & Ooi, E. E. A potential silver lining of delaying the second dose. Nat. Immunol. 23, 349–351 (2022).
Lee, J. H. et al. Long-primed germinal centres with enduring affinity maturation and clonal migration. Nature 609, 998–1004 (2022).
Hall, V. G. et al. Delayed-interval BNT162b2 mRNA COVID-19 vaccination enhances humoral immunity and induces robust T cell responses. Nat. Immunol. 23, 380–385 (2022).
Kim, W. et al. Germinal centre-driven maturation of B cell response to mRNA vaccination. Nature 604, 141–145 (2022).
Liu, X. et al. Persistence of immunogenicity after seven COVID-19 vaccines given as third dose boosters following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK: three month analyses of the COV-BOOST trial. J. Infect. 84, 795–813 (2022).
Styles, T. M. et al. V2 hotspot optimized MVA vaccine expressing stabilized HIV-1 Clade C envelope Gp140 delays acquisition of heterologous Clade C Tier 2 challenges in Mamu-A*01 negative Rhesus Macaques. Front. Immunol. 13, 914969 (2022).
Ziegler, L. et al. Differences in SARS-CoV-2 specific humoral and cellular immune responses after contralateral and ipsilateral COVID-19 vaccination. EBioMedicine 95, 104743 (2023).
Bollimpelli, V. S. et al. Intradermal but not intramuscular modified vaccinia Ankara immunizations protect against intravaginal tier2 simian-human immunodeficiency virus challenges in female macaques. Nat. Commun. 14, 4789 (2023).
Dhenni, R. et al. Macrophages direct location-dependent recall of B cell memory to vaccination. Cell 188, 3477–96.e22 (2025).
Tam, H. H. et al. Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination. Proc. Natl Acad. Sci. USA 113, E6639–E6648 (2016).
Baumjohann, D. et al. Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype. Immunity 38, 596–605 (2013).
Zimmermann, P. & Curtis, N. Factors that influence the immune response to vaccination. Clin. Microbiol. Rev. 32, e00084–18 (2019).
Pieren, D. K. J., Boer, M. C. & de Wit, J. The adaptive immune system in early life: the shift makes it count. Front Immunol. 13, 1031924 (2022).
Wang, Y., Dong, C., Han, Y., Gu, Z. & Sun, C. Immunosenescence, aging and successful aging. Front Immunol. 13, 942796 (2022).
Xie, J. et al. Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes. Nat. Commun. 15, 4031 (2024).
Augusto, D. G. et al. A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection. Nature 620, 128–136 (2023).
Tsang, J. S. et al. Improving vaccine-induced immunity: can baseline predict outcome?. Trends Immunol. 41, 457–465 (2020).
Linderman, S. L. & Hensley, S. E. Antibodies with ‘original antigenic sin’ properties are valuable components of secondary immune responses to influenza viruses. PLoS Pathog. 12, e1005806 (2016).
Zhang, Y. et al. Germinal center B cells govern their own fate via antibody feedback. J. Exp. Med. 210, 457–464 (2013).
Cao, Y. et al. Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution. Nature 614, 521–529 (2023).
Zhao, M. et al. Serum neutralizing antibody titers 12 months after coronavirus disease 2019 messenger RNA vaccination: correlation to clinical variables in an adult, US population. Clin. Infect. Dis. 76, e391–e399 (2023).
Carabelli, A. M. et al. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat. Rev. Microbiol. 21, 162–177 (2023).
Nuwarda, R. F., Alharbi, A. A. & Kayser, V. An overview of influenza viruses and vaccines. Vaccines (Basel). 9, 1032 (2021).
Kaslow, D. C. Force of infection: a determinant of vaccine efficacy?. NPJ Vaccines 6, 51 (2021).
Collier, A. Y. et al. Differential kinetics of immune responses elicited by Covid-19 vaccines. N. Engl. J. Med. 385, 2010–2012 (2021).
Pegu, A. et al. Durability of mRNA-1273 vaccine-induced antibodies against SARS-CoV-2 variants. Science 373, 1372–1377 (2021).
Falsey, A. R. et al. SARS-CoV-2 neutralization with BNT162b2 vaccine dose 3. N. Engl. J. Med. 385, 1627–1629 (2021).
Mihaylova, A. et al. Durability of humoral and cell-mediated immune response after SARS-CoV-2 mRNA vaccine administration. J. Med. Virol. 95, e28360 (2023).
Puranik, A. et al. Durability analysis of the highly effective mRNA-1273 vaccine against COVID-19. PNAS Nexus 1, pgac058 (2022).
Terreri, S. et al. Persistent B cell memory after SARS-CoV-2 vaccination is functional during breakthrough infections. Cell Host Microbe 30, 400–8.e4 (2022).
Goel, R. R. et al. mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern. Science 374, abm0829 (2021).
Korosec, C. S. et al. Long-term durability of immune responses to the BNT162b2 and mRNA-1273 vaccines based on dosage, age and sex. Sci. Rep. 12, 21232 (2022).
Suthar, M. S. et al. Durability of immune responses to the BNT162b2 mRNA vaccine. Med 3, 25–27 (2022).
Hansen, L. et al. Durable immune responses after BNT162b2 vaccination in home-dwelling old adults. Vaccin. X 13, 100262 (2023).
Israel, A. et al. Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection. Vaccines (Basel). 10, 64 (2021).
Herring, M. K. et al. Severe acute respiratory syndrome coronavirus 2 infection history and antibody response to 3 coronavirus disease 2019 messenger RNA vaccine doses. Clin. Infect. Dis. 76, 1822–1831 (2023).
Agallou, M. et al. Antibody and T-cell subsets analysis unveils an immune profile heterogeneity mediating long-term responses in individuals vaccinated against SARS-CoV-2. J. Infect. Dis. 227, 353–363 (2023).
Pajon, R. et al. SARS-CoV-2 Omicron variant neutralization after mRNA-1273 booster vaccination. N. Engl. J. Med. 386, 1088–1091 (2022).
Doria-Rose, N. et al. Antibody persistence through 6 months after the second dose of mRNA-1273 vaccine for Covid-19. N. Engl. J. Med. 384, 2259–2261 (2021).
Steensels, D., Pierlet, N., Penders, J., Mesotten, D. & Heylen, L. Comparison of SARS-CoV-2 antibody response following vaccination with BNT162b2 and mRNA-1273. JAMA 326, 1533–1535 (2021).
Bajema, K. L. et al. Comparative effectiveness and antibody responses to Moderna and Pfizer-BioNTech COVID-19 vaccines among hospitalized veterans—five veterans affairs medical centers, United States, February 1–September 30, 2021. MMWR Morb. Mortal. Wkly Rep. 70, 1700–1705 (2021).
Chalkias, S. et al. Safety, immunogenicity and antibody persistence of a bivalent Beta-containing booster vaccine against COVID-19: a phase 2/3 trial. Nat. Med. 28, 2388–2397 (2022).
Regev-Yochay, G. et al. Efficacy of a fourth dose of Covid-19 mRNA vaccine against Omicron. N. Engl. J. Med. 386, 1377–1380 (2022).
Xia, H. et al. Neutralization and durability of 2 or 3 doses of the BNT162b2 vaccine against Omicron SARS-CoV-2. Cell Host Microbe 30, 485–8.e3 (2022).
Chen, X. et al. Longitudinal neutralizing and functional antibody responses to severe acute respiratory syndrome coronavirus 2 variants following messenger RNA coronavirus disease 2019 vaccination. Open Forum Infect. Dis. 10, ofad167 (2023).
Srivastava, K. et al. SARS-CoV-2-infection- and vaccine-induced antibody responses are long lasting with an initial waning phase followed by a stabilization phase. Immunity 57, 587–99.e4 (2024).
Nakagama, S. et al. Age-adjusted impact of prior COVID-19 on SARS-CoV-2 mRNA vaccine response. Front Immunol. 14, 1087473 (2023).
Breznik, J. A. et al. Early humoral and cellular responses after bivalent SARS-CoV-2 mRNA-1273.214 vaccination in long-term care and retirement home residents in Ontario, Canada: an observational cohort study. J. Med. Virol. 95, e29170 (2023).
Ciccone, E. J. et al. Magnitude and durability of the antibody response to mRNA-based vaccination among SARS-CoV-2 seronegative and seropositive health care personnel. Open Forum Infect. Dis. 11, ofae009 (2024).
Walory, J., Ksiazek, I., Karynski, M. & Baraniak, A. Twenty-month monitoring of humoral immune response to BNT162b2 vaccine: antibody kinetics, breakthrough infections, and adverse effects. Vaccines (Basel). 11, 1578 (2023).
Epsi, N. J. et al. Understanding “hybrid immunity”: comparison and predictors of humoral immune responses to severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) vaccines. Clin. Infect. Dis. 76, e439–e449 (2023).
Owsianka, I. et al. SARS-CoV-2 antibody response after mRNA vaccination in healthcare workers with and without previous COVID-19, a follow-up study from a university hospital in Poland during 6 months 2021. Front. Immunol. 13, 1071204 (2022).
Walls, A. C. et al. SARS-CoV-2 breakthrough infections elicit potent, broad, and durable neutralizing antibody responses. Cell 185, 872–80.e3 (2022).
Oda, Y. et al. Persistence of immune responses of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2. Lancet Infect. Dis. 24, 341–343 (2024).
Oda, Y. et al. Immunogenicity and safety of a booster dose of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2 mRNA COVID-19 vaccine: a double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet Infect. Dis. 24, 351–360 (2024).
Ho, N. T. et al. Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a and 3b randomized, controlled trials. Nat. Commun. 15, 4081 (2024).
Oda, Y. et al. 12-month persistence of immune responses to self-amplifying mRNA COVID-19 vaccines: ARCT-154 versus BNT162b2 vaccine. Lancet Infect. Dis. 24, e729–e731 (2024).
Launay, O. et al. Immunogenicity and safety of beta-adjuvanted recombinant booster vaccine. N. Engl. J. Med. 387, 374–376 (2022).
Sridhar, S. et al. Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study. Lancet Infect. Dis. 22, 636–648 (2022).
de Bruyn, G. et al. Safety and immunogenicity of a variant-adapted SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant as a booster in adults primed with authorized vaccines: a phase 3, parallel-group study. EClinicalMedicine 62, 102109 (2023).
Dayan, G. H. et al. Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in adults: a phase 3, parallel, randomised, modified double-blind, placebo-controlled trial. Lancet Respir. Med. 11, 975–990 (2023).
Charland, N. et al. Safety and immunogenicity of an AS03-adjuvanted plant-based SARS-CoV-2 vaccine in adults with and without comorbidities. NPJ Vaccines 7, 142 (2022).
Garrido, C. et al. SARS-CoV-2 vaccines elicit durable immune responses in infant rhesus macaques. Sci. Immunol. 6, eabj3684 (2021).
Milligan, E. C. et al. Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge 1 year later. Sci. Transl. Med. 15, eadd6383 (2023).
Stertman, L. et al. The Matrix-M adjuvant: A critical component of vaccines for the 21(st) century. Hum. Vaccin Immunother. 19, 2189885 (2023).
Lenart, K. et al. Three immunizations with Novavax’s protein vaccines increase antibody breadth and provide durable protection from SARS-CoV-2. NPJ Vaccines 9, 17 (2024).
Zhang, Z. et al. Humoral and cellular immune memory to four COVID-19 vaccines. Cell 185, 2434–51.e17 (2022).
Muecksch, F. et al. Increased memory B cell potency and breadth after a SARS-CoV-2 mRNA boost. Nature 607, 128–134 (2022).
Cho, A. et al. Anti-SARS-CoV-2 receptor-binding domain antibody evolution after mRNA vaccination. Nature 600, 517–522 (2021).
Tarke, A. et al. SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron. Cell 185, 847–59.e11 (2022).
Mudd, P. A. et al. SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans. Cell 185, 603–13.e15 (2022).
Turner, J. S. et al. SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Nature 596, 109–113 (2021).
Roltgen, K. et al. Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination. Cell 185, 1025–40.e14 (2022).
Guerrera, G. et al. BNT162b2 vaccination induces durable SARS-CoV-2-specific T cells with a stem cell memory phenotype. Sci. Immunol. 6, eabl5344 (2021).
Lozano-Rodriguez, R. et al. mRNA-1273 boost after BNT162b2 vaccination generates comparable SARS-CoV-2-specific functional responses in naive and COVID-19-recovered individuals. Front. Immunol. 14, 1136029 (2023).
Carretero, D. et al. SARS-CoV-2-Spike T-cell response after receiving one or two Wuhan-Hu-1-based mRNA COVID-19 vaccine booster doses in elderly nursing home residents. J. Med. Virol. 96, e29790 (2024).
Nelson, R. W. et al. SARS-CoV-2 epitope-specific CD4(+) memory T cell responses across COVID-19 disease severity and antibody durability. Sci. Immunol. 7, eabl9464 (2022).
Hurme, A. et al. Long-lasting T cell responses in BNT162b2 COVID-19 mRNA vaccinees and COVID-19 convalescent patients. Front Immunol. 13, 869990 (2022).
Borcherding, N. et al. CD4(+) T cells exhibit distinct transcriptional phenotypes in the lymph nodes and blood following mRNA vaccination in humans. Nat. Immunol. 25, 1731–1741 (2024).
Lederer, K. et al. Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals. Cell 185, 1008–24.e15 (2022).
Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).
Thomas, S. J. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months. N. Engl. J. Med. 385, 1761–1773 (2021).
Frenck, R. W. Jr et al. Safety, immunogenicity, and efficacy of the BNT162b2 Covid-19 vaccine in adolescents. N. Engl. J. Med. 385, 239–250 (2021).
Munoz, F. M. et al. Evaluation of BNT162b2 Covid-19 vaccine in children younger than 5 years of age. N. Engl. J. Med. 388, 621–634 (2023).
El Sahly, H. M. et al. Efficacy of the mRNA-1273 SARS-CoV-2 vaccine at completion of blinded phase. N. Engl. J. Med. 385, 1774–1785 (2021).
Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).
Heath, P. T. et al. Safety and efficacy of NVX-CoV2373 Covid-19 vaccine. N. Engl. J. Med. 385, 1172–1183 (2021).
Dunkle, L. M. et al. Efficacy and safety of NVX-CoV2373 in adults in the United States and Mexico. N. Engl. J. Med. 386, 531–543 (2022).
Follmann, D. et al. Durability of protection against COVID-19 through the Delta surge for the NVX-CoV2373 vaccine. Clin. Infect. Dis. 79, 78–85 (2024).
Mateo-Urdiales, A. et al. Estimated effectiveness of a primary cycle of protein recombinant vaccine NVX-CoV2373 against COVID-19. JAMA Netw. Open 6, e2336854 (2023).
Krammer, F. The role of vaccines in the COVID-19 pandemic: what have we learned?. Semin Immunopathol. 45, 451–468 (2024).
Lin, D. Y. et al. Association of primary and booster vaccination and prior infection with SARS-CoV-2 infection and severe COVID-19 outcomes. JAMA 328, 1415–1426 (2022).
Wu, N. et al. Long-term effectiveness of COVID-19 vaccines against infections, hospitalisations, and mortality in adults: findings from a rapid living systematic evidence synthesis and meta-analysis up to December, 2022. Lancet Respir. Med. 11, 439–452 (2023).
Link-Gelles, R. et al. Estimates of bivalent mRNA vaccine durability in preventing COVID-19-associated hospitalization and critical illness among adults with and without immunocompromising conditions—VISION Network, September 2022–April 2023. MMWR Morb. Mortal. Wkly Rep. 72, 579–588 (2023).
Tenforde, M. W. et al. Sustained effectiveness of Pfizer-BioNTech and Moderna vaccines against COVID-19 associated hospitalizations among adults—United States, March–July 2021. MMWR Morb. Mortal. Wkly Rep. 70, 1156–1162 (2021).
Goldberg, Y. et al. Waning Immunity after the BNT162b2 Vaccine in Israel. N. Engl. J. Med. 385, e85 (2021).
Andrews, N. et al. Duration of protection against mild and severe disease by Covid-19 vaccines. N. Engl. J. Med. 386, 340–350 (2022).
Ferdinands, J. M. et al. Waning 2-dose and 3-dose effectiveness of mRNA vaccines against COVID-19-associated emergency department and urgent care encounters and hospitalizations among adults during periods of Delta and Omicron variant predominance—VISION Network, 10 States, August 2021–January 2022. MMWR Morb. Mortal. Wkly Rep. 71, 255–263 (2022).
DeCuir, J. et al. Effectiveness of monovalent mRNA COVID-19 vaccination in preventing COVID-19-associated invasive mechanical ventilation and death among immunocompetent adults during the Omicron variant period—IVY Network, 19 U.S. States, February 1, 2022–January 31, 2023. MMWR Morb. Mortal. Wkly Rep. 72, 463–468 (2023).
Kirsebom, F. C. M., Andrews, N., Stowe, J., Ramsay, M. & Lopez Bernal, J. Duration of protection of ancestral-strain monovalent vaccines and effectiveness of bivalent BA.1 boosters against COVID-19 hospitalisation in England: a test-negative case-control study. Lancet Infect. Dis. 23, 1235–1243 (2023).
Wherry, E. J. & Barouch, D. H. T cell immunity to COVID-19 vaccines. Science 377, 821–822 (2022).
Li, Y. et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis. Lancet 399, 2047–2064 (2022).
Kenmoe, S. & Nair, H. The disease burden of respiratory syncytial virus in older adults. Curr. Opin. Infect. Dis. 37, 129–136 (2024).
Fujiogi, M. et al. Trends in bronchiolitis hospitalizations in the United States: 2000–2016. Pediatrics 144, e20192614 (2019).
Snow, K. D. et al. Trends in emergency department visits for bronchiolitis, 1993–2019. Pediatr. Pulmonol. 59, 930–937 (2024).
Shaw, C. A. et al. Safety, tolerability and immunogenicity of a mRNA-based RSV vaccine in healthy young adults in a phase 1 clinical trial. J. Infect. Dis. 230, e637–e646 (2024).
Fitz-Patrick, D. et al. Safety and immunogenicity of an mRNA-based RSV vaccine in Japanese older adults aged≥ 60 years: a phase 1, randomized, observer-blind, placebo-controlled trial. Respir. Investig. 62, 1037–1043 (2024).
Shaw, C. A. et al. Safety and immunogenicity of an mRNA-based RSV vaccine including a 12-month booster in a phase I clinical trial in healthy older adults. J. Infect. Dis. 230, e647–e656 (2024).
Wilson, E. et al. Efficacy and safety of an mRNA-based RSV PreF vaccine in older adults. N. Engl. J. Med. 389, 2233–2244 (2023).
Sacconnay, L. et al. The RSVPreF3-AS01 vaccine elicits broad neutralization of contemporary and antigenically distant respiratory syncytial virus strains. Sci. Transl. Med. 15, eadg6050 (2023).
Leroux-Roels, I. et al. Safety and immunogenicity of a respiratory syncytial virus prefusion F (RSVPreF3) candidate vaccine in older adults: phase 1/2 randomized clinical trial. J. Infect. Dis. 227, 761–772 (2023).
Schwarz, T. F. et al. Immunogenicity and safety following one dose of AS01E-adjuvanted respiratory syncytial virus prefusion F protein vaccine in older adults: a phase 3 trial. J. Infect. Dis. 230, e102–e110 (2024).
Papi, A. et al. Respiratory syncytial virus prefusion F protein vaccine in older adults. N. Engl. J. Med. 388, 595–608 (2023).
Ison, M. G. et al. Efficacy and safety of respiratory syncytial virus (RSV) prefusion F protein vaccine (RSVPreF3 OA) in older adults over 2 RSV seasons. Clin. Infect. Dis. 78, 1732–1744 (2024).
Paget, J. et al. Global mortality associated with seasonal influenza epidemics: new burden estimates and predictors from the GLaMOR Project. J. Glob. Health 9, 020421 (2019).
Macias, A. E. et al. The disease burden of influenza beyond respiratory illness. Vaccine 39, A6–A14 (2021).
Ananworanich, J. et al. Safety and immunogenicity of mRNA-1010, an investigational seasonal influenza vaccine, in healthy adults: final results from a Phase 1/2 randomized trial. J. Infect. Dis. 231, e113–e122 (2025).
Soens, M. et al. A phase 3 randomized safety and immunogenicity trial of mRNA-1010 seasonal influenza vaccine in adults. Vaccine 50, 126847 (2025).
Lee, I. T. et al. Safety and immunogenicity of a phase 1/2 randomized clinical trial of a quadrivalent, mRNA-based seasonal influenza vaccine (mRNA-1010) in healthy adults: interim analysis. Nat. Commun. 14, 3631 (2023).
Esposito, S. et al. Immunogenicity and safety of an MF59-adjuvanted quadrivalent seasonal influenza vaccine in young children at high risk of influenza-associated complications: a Phase III, randomized, observer-blind, multicenter clinical trial. Pediatr. Infect. Dis. J. 39, e185–e191 (2020).
Nolan, T. et al. Enhanced and persistent antibody response against homologous and heterologous strains elicited by a MF59-adjuvanted influenza vaccine in infants and young children. Vaccine 32, 6146–6156 (2014).
Vesikari, T. et al. Efficacy, immunogenicity, and safety evaluation of an MF59-adjuvanted quadrivalent influenza virus vaccine compared with non-adjuvanted influenza vaccine in children: a multicentre, randomised controlled, observer-blinded, phase 3 trial. Lancet Respir. Med. 6, 345–356 (2018).
Vesikari, T. et al. Oil-in-water emulsion adjuvant with influenza vaccine in young children. N. Engl. J. Med. 365, 1406–1416 (2011).
Frey, S. E. et al. Comparison of the safety and immunogenicity of an MF59(R)-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects. Vaccine 32, 5027–5034 (2014).
Song, J. Y. et al. Long-term and cross-reactive immunogenicity of inactivated trivalent influenza vaccine in the elderly: MF59-adjuvanted vaccine versus unadjuvanted vaccine. J. Med. Virol. 85, 1591–1597 (2013).
Ruiz-Palacios, G. M. et al. Immunogenicity of AS03-adjuvanted and non-adjuvanted trivalent inactivated influenza vaccines in elderly adults: a Phase 3, randomized trial and post-hoc correlate of protection analysis. Hum. Vaccin Immunother. 12, 3043–3055 (2016).
Smith, C. L. et al. Humoral and cellular immunity induced by adjuvanted and standard trivalent influenza vaccine in older nursing home residents. J. Infect. Dis. 228, 704–714 (2023).
McElhaney, J. E. et al. AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. Lancet Infect. Dis. 13, 485–496 (2013).
Kenneson, A. & Cannon, M. J. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev. Med. Virol. 17, 253–276 (2007).
Griffiths, P. & Reeves, M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat. Rev. Microbiol. 19, 759–773 (2021).
Wu, K. et al. Characterization of humoral and cellular immunologic responses to an mRNA-based human cytomegalovirus vaccine from a phase 1 trial of healthy adults. J. Virol. 98, e0160323 (2024).
Fierro, C. et al. Safety and immunogenicity of a messenger RNA-based cytomegalovirus vaccine in healthy adults: results from a phase 1, randomized, clinical trial. J Infect Dis. 230, e668–e678 (2024).
Hu, X. et al. Human cytomegalovirus mRNA-1647 vaccine candidate elicits potent and broad neutralization and higher antibody-dependent cellular cytotoxicity responses than the gB/MF59 vaccine. J. Infect. Dis. 230, 455–466 (2024).
Plotkin, S. A. et al. The status of vaccine development against the human cytomegalovirus. J. Infect. Dis. 221, S113–S122 (2020).
Pass, R. F. et al. Vaccine prevention of maternal cytomegalovirus infection. N. Engl. J. Med. 360, 1191–1199 (2009).
Bernstein, D. I. et al. Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial. Vaccine 34, 313–319 (2016).
Sabbaj, S., Pass, R. F., Goepfert, P. A. & Pichon, S. Glycoprotein B vaccine is capable of boosting both antibody and CD4 T-cell responses to cytomegalovirus in chronically infected women. J. Infect. Dis. 203, 1534–1541 (2011).
Scholte, L. L. S. et al. Ultrasound-guided lymph node fine-needle aspiration for evaluating post-vaccination germinal center responses in humans. STAR Protoc. 4, 102576 (2023).
Schattgen, S. A. et al. Influenza vaccination stimulates maturation of the human T follicular helper cell response. Nat. Immunol. 25, 1742–1753 (2024).
Nguyen, D. C. et al. SARS-CoV-2-specific plasma cells are not durably established in the bone marrow long-lived compartment after mRNA vaccination. Nat. Med. 31, 235–244 (2025).
Wimmers, F. & Pulendran, B. Emerging technologies for systems vaccinology – multi-omics integration and single-cell (epi)genomic profiling. Curr. Opin. Immunol. 65, 57–64 (2020).
Bunyavanich, S. et al. Analytical challenges in omics research on asthma and allergy: a National Institute of Allergy and Infectious Diseases workshop. J. Allergy Clin. Immunol. 153, 954–968 (2024).
Raita, Y. et al. Integrated omics endotyping of infants with respiratory syncytial virus bronchiolitis and risk of childhood asthma. Nat. Commun. 12, 3601 (2021).
Raita, Y. et al. Integrated-omics endotyping of infants with rhinovirus bronchiolitis and risk of childhood asthma. J. Allergy Clin. Immunol. 147, 2108–2117 (2021).
Arunachalam, P. S. et al. Systems vaccinology of the BNT162b2 mRNA vaccine in humans. Nature 596, 410–416 (2021).
Pulendran, B. & Davis, M. M. The science and medicine of human immunology. Science 369, eaay4014 (2020).
Hagan, T. et al. Transcriptional atlas of the human immune response to 13 vaccines reveals a common predictor of vaccine-induced antibody responses. Nat. Immunol. 23, 1788–1798 (2022).
Fourati, S. et al. Pan-vaccine analysis reveals innate immune endotypes predictive of antibody responses to vaccination. Nat. Immunol. 23, 1777–1787 (2022).
Ravindran, R. et al. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science 343, 313–317 (2014).
Zhu, Z., Hasegawa, K., Camargo, C. A. Jr & Liang, L. Investigating asthma heterogeneity through shared and distinct genetics: Insights from genome-wide cross-trait analysis. J. Allergy Clin. Immunol. 147, 796–807 (2021).
Pulendran, B., S Arunachalam, P. & O’Hagan, D. T. Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov. 20, 454–475 (2021).
Pulendran, B. Systems vaccinology: probing humanity’s diverse immune systems with vaccines. Proc. Natl Acad. Sci. USA 111, 12300–12306 (2014).
Vandereyken, K., Sifrim, A., Thienpont, B. & Voet, T. Methods and applications for single-cell and spatial multi-omics. Nat. Rev. Genet. 24, 494–515 (2023).
Sharma, V. K., Sharma, I. & Glick, J. The expanding role of mass spectrometry in the field of vaccine development. Mass Spectrom. Rev. 39, 83–104 (2020).
Cortese, M. et al. System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans. Nat. Immunol. 26, 116–130 (2025).
Rappuoli, R., Alter, G. & Pulendran, B. Transforming vaccinology. Cell 187, 5171–5194 (2024).
Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021).
Kumar, A. et al. The mRNA vaccine development landscape for infectious diseases. Nat. Rev. Drug Discov. 21, 333–334 (2022).
Verbeke, R., Hogan, M. J., Lore, K. & Pardi, N. Innate immune mechanisms of mRNA vaccines. Immunity 55, 1993–2005 (2022).
Cheng, C. W. et al. Low-sugar universal mRNA vaccine against coronavirus variants with deletion of glycosites in the S2 or stem of SARS-CoV-2 spike messenger RNA (mRNA). Proc. Natl Acad. Sci. USA 120, e2314392120 (2023).
Moss, P. The T cell immune response against SARS-CoV-2. Nat. Immunol. 23, 186–193 (2022).
Pullen, R. H. 3rd et al. A predictive model of vaccine reactogenicity using data from an in vitro human innate immunity assay system. J. Immunol. 212, 904–916 (2024).
Kyriakidis, N. C., Lopez-Cortes, A., Gonzalez, E. V., Grimaldos, A. B. & Prado, E. O. SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. NPJ Vaccines 6, 28 (2021).
Lee, B., Nanishi, E., Levy, O. & Dowling, D. J. Precision vaccinology approaches for the development of adjuvanted vaccines targeted to distinct vulnerable populations. Pharmaceutics 15, 1766 (2023).
Feenstra, B. et al. Common variants associated with general and MMR vaccine-related febrile seizures. Nat. Genet 46, 1274–1282 (2014).
Lewnard, J. A. & Cobey, S. Immune history and influenza vaccine effectiveness. Vaccines (Basel). 6, 28 (2018).
Agyeman, A. S. et al. US FDA public meeting: identification of concepts and terminology for multicomponent biomarkers. Biomark. Med. 17, 523–531 (2023).
Nanishi, E., Dowling, D. J. & Levy, O. Toward precision adjuvants: optimizing science and safety. Curr. Opin. Pediatr. 32, 125–138 (2020).