Abstract
Vaccines play a critical role in the prevention of life-threatening infectious disease. However, the development of effective vaccines against many immune-evading pathogens such as HIV has proven challenging, and existing vaccines against some diseases such as tuberculosis and malaria have limited efficacy. The historically slow rate of vaccine development and limited pan-variant immune responses also limit existing vaccine utility against rapidly emerging and mutating pathogens such as influenza and SARS-CoV-2. Additionally, reactogenic effects can contribute to vaccine hesitancy, further undermining the ability of vaccination campaigns to generate herd immunity. These limitations are fuelling the development of novel vaccine technologies to more effectively combat infectious diseases. Towards this end, advances in vaccine delivery systems, adjuvants, antigens and other technologies are paving the way for the next generation of vaccines. This Review focuses on recent advances in synthetic vaccine systems and their associated challenges, highlighting innovation in the field of nano- and nucleic acid-based vaccines.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
27,99 € / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
209,00 € per year
only 17,42 € per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Morens, D. M. & Fauci, A. S. Emerging pandemic diseases: how we got to COVID-19. Cell 182, 1077–1092 (2020).
Toor, J. et al. Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world. eLife 10, e67635 (2021).
Fan, V. Y., Jamison, D. T. & Summers, L. H. Pandemic risk: how large are the expected losses? Bull. World Health Organ. 96, 129–134 (2018).
Mascola, J. R. & Fauci, A. S. Novel vaccine technologies for the 21st century. Nat. Rev. Immunol. 20, 87–88 (2020).
Excler, J. L., Saville, M., Berkley, S. & Kim, J. H. Vaccine development for emerging infectious diseases. Nat. Med. 27, 591–600 (2021).
Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021).
Haynes, B. F. et al. Prospects for a safe COVID-19 vaccine. Sci. Transl. Med. 12, eabe0948 (2020).
Roth, G. A. et al. Designing spatial and temporal control of vaccine responses. Nat. Rev. Mater. 7, 174–195 (2022).
Cirelli, K. M. et al. Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance. Cell 177, 1153–1171.e28 (2019).
Satti, I. et al. Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial. Lancet Infect. Dis. 14, 939–946 (2014).
Payne, R. P. et al. Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine. Cell 184, 5699–5714.e11 (2021).
Wei, C. J. et al. Next-generation influenza vaccines: opportunities and challenges. Nat. Rev. Drug Discov. 19, 239–252 (2020).
Scheaffer, S. M. et al. Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice. Nat. Med. 29, 247–257 (2023).
Graham, B. S., Gilman, M. S. A. & McLellan, J. S. Structure-based vaccine antigen design. Annu. Rev. Med. 70, 91–104 (2019).
Rappuoli, R., Bottomley, M. J., D’Oro, U., Finco, O. & De Gregorio, E. Reverse vaccinology 2.0: human immunology instructs vaccine antigen design. J. Exp. Med. 213, 469–481 (2016).
Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).
Jeyanathan, M. et al. Immunological considerations for COVID-19 vaccine strategies. Nat. Rev. Immunol. 20, 615–632 (2020).
Singh, A. Eliciting B cell immunity against infectious diseases using nanovaccines. Nat. Nanotechnol. 16, 16–24 (2021).
Irvine, D. J., Swartz, M. A. & Szeto, G. L. Engineering synthetic vaccines using cues from natural immunity. Nat. Mater. 12, 978–990 (2013).
Verbeke, R., Hogan, M. J., Loré, K. & Pardi, N. Innate immune mechanisms of mRNA vaccines. Immunity 55, 1993–2005 (2022).
Diamond, M. S. & Kanneganti, T.-D. Innate immunity: the first line of defense against SARS-CoV-2. Nat. Immunol. 23, 165–176 (2022).
Ziogas, A. & Netea, M. G. Trained immunity-related vaccines: innate immune memory and heterologous protection against infections. Trends Mol. Med. 28, 497–512 (2022).
Mulder, W. J. M., Ochando, J., Joosten, L. A. B., Fayad, Z. A. & Netea, M. G. Therapeutic targeting of trained immunity. Nat. Rev. Drug Discov. 18, 553–566 (2019).
Gasteiger, G. et al. Cellular innate immunity: an old game with new players. J. Innate Immun. 9, 111–125 (2017).
Worbs, T., Hammerschmidt, S. I. & Förster, R. Dendritic cell migration in health and disease. Nat. Rev. Immunol. 17, 30–48 (2017).
Swartz, M. A., Hubbell, J. A. & Reddy, S. T. Lymphatic drainage function and its immunological implications: from dendritic cell homing to vaccine design. Semin. Immunol. 20, 147–156 (2008).
Rauch, S., Jasny, E., Schmidt, K. E. & Petsch, B. New vaccine technologies to combat outbreak situations. Front. Immunol. 9, 1963 (2018).
Brooks, J. T., Marks, P., Goldstein, R. H. & Walensky, R. P. Intradermal vaccination for monkeypox — benefits for individual and public health. N. Engl. J. Med. 387, 1151–1153 (2022).
Alu, A. et al. Intranasal COVID-19 vaccines: from bench to bed. EBioMedicine 76, 103841 (2022).
Bull, N. C. et al. Enhanced protection conferred by mucosal BCG vaccination associates with presence of antigen-specific lung tissue-resident PD-1+ KLRG1− CD4+ T cells. Mucosal Immunol. 12, 555–564 (2019).
Zhao, J. et al. Airway memory CD4+ T cells mediate protective immunity against emerging respiratory coronaviruses. Immunity 44, 1379–1391 (2016).
Carter, N. J. & Curran, M. P. Live attenuated influenza vaccine (FluMist®; FluenzTM). Drugs 71, 1591–1622 (2011).
Baldeon Vaca, G. et al. Intranasal mRNA-LNP vaccination protects hamsters from SARS-CoV-2 infection. Sci. Adv. 9, eadh1655 (2023).
Mao, T. et al. Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses. Science 378, eabo2523 (2024).
Hartwell, B. L. et al. Intranasal vaccination with lipid-conjugated immunogens promotes antigen transmucosal uptake to drive mucosal and systemic immunity. Sci. Transl. Med. 14, eabn1413 (2024).
Ganley, M. et al. mRNA vaccine against malaria tailored for liver-resident memory T cells. Nat. Immunol. 24, 1487–1498 (2023).
Darrah, P. A. et al. Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature 577, 95–102 (2020). This study investigates the association between BCG vaccine efficacy and its administration route, revealing that intravenous BCG provides exceptional protection against Mycobacterium tuberculosis infection.
Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019).
Prins, M. L. M. et al. Immunogenicity and reactogenicity of intradermal mRNA-1273 SARS-CoV-2 vaccination: a non-inferiority, randomized-controlled trial. NPJ Vaccines 9, 1 (2024).
Syenina, A. et al. Adverse effects following anti–COVID-19 vaccination with mRNA-based BNT162b2 are alleviated by altering the route of administration and correlate with baseline enrichment of T and NK cell genes. PLoS Biol. 20, e3001643 (2022).
Eshaghi, B. et al. The role of engineered materials in mucosal vaccination strategies. Nat. Rev. Mater. 9, 29–45 (2024).
Hsieh, C. L. et al. Structure-based design of prefusion-stabilized SARS-CoV-2 spikes. Science 369, 1501–1505 (2020).
McLellan, J. S. et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 342, 592–598 (2013).
Lu, M. et al. SARS-CoV-2 prefusion spike protein stabilized by six rather than two prolines is more potent for inducing antibodies that neutralize viral variants of concern. Proc. Natl Acad. Sci. USA 119, e2110105119 (2022).
Milder, F. J. et al. Universal stabilization of the influenza hemagglutinin by structure-based redesign of the pH switch regions. Proc. Natl Acad. Sci. USA 119, e2115379119 (2022).
Kulp, D. W. et al. Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding. Nat. Commun. 8, 1655 (2017).
Sanders, R. W. et al. A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. PLoS Pathog. 9, e1003618 (2013).
Nachbagauer, R. et al. A universal influenza virus vaccine candidate confers protection against pandemic H1N1 infection in preclinical ferret studies. NPJ Vaccines 2, 26 (2017).
Steichen, J. M. et al. HIV vaccine design to target germline precursors of glycan-dependent broadly neutralizing antibodies. Immunity 45, 483–496 (2016).
Dubrovskaya, V. et al. Vaccination with glycan-modified HIV NFL envelope trimer-liposomes elicits broadly neutralizing antibodies to multiple sites of vulnerability. Immunity 51, 915–929.e7 (2019).
Walker, L. M. & Burton, D. R. Passive immunotherapy of viral infections: ‘super-antibodies’ enter the fray. Nat. Rev. Immunol. 18, 297–308 (2018).
Haynes, B. F. et al. Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies. Nat. Rev. Immunol. 23, 142–158 (2023).
Xu, D. et al. Vaccine design via antigen reorientation. Nat. Chem. Biol. 20, 1012–1021 (2024).
Hsieh, C.-L. et al. Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge. Nat. Commun. 15, 1553 (2024).
Pang, W. et al. A variant-proof SARS-CoV-2 vaccine targeting HR1 ___domain in S2 subunit of spike protein. Cell Res. 32, 1068–1085 (2022).
Patterson, D. P., Rynda-Apple, A., Harmsen, A. L., Harmsen, A. G. & Douglas, T. Biomimetic antigenic nanoparticles elicit controlled protective immune response to influenza. ACS Nano 7, 3036–3044 (2013).
Batista, F. D., Iber, D. & Neuberger, M. S. B cells acquire antigen from target cells after synapse formation. Nature 411, 489–494 (2001).
Trombetta, E. S. & Mellman, I. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23, 975–1028 (2005).
Bale, J. B. et al. Accurate design of megadalton-scale two-component icosahedral protein complexes. Science 353, 389–394 (2016).
Marcandalli, J. et al. Induction of potent neutralizing antibody responses by a designed protein nanoparticle vaccine for respiratory syncytial virus. Cell 176, 1420–1431.e17 (2019).
Brouwer, P. J. M. et al. Enhancing and shaping the immunogenicity of native-like HIV-1 envelope trimers with a two-component protein nanoparticle. Nat. Commun. 10, 4272 (2019).
Boyoglu-Barnum, S. et al. Quadrivalent influenza nanoparticle vaccines induce broad protection. Nature 592, 623–628 (2021).
Walls, A. C. et al. Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2. Cell 183, 1367–1382.e17 (2020).
Brouwer, P. J. M. et al. Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection. Cell 184, 1188–1200.e19 (2021).
Walls, A. C. et al. Elicitation of broadly protective sarbecovirus immunity by receptor-binding ___domain nanoparticle vaccines. Cell 184, 5432–5447.e16 (2021).
Shin, M. D. et al. COVID-19 vaccine development and a potential nanomaterial path forward. Nat. Nanotechnol. 15, 646–655 (2020).
Fries, C. N. et al. Advances in nanomaterial vaccine strategies to address infectious diseases impacting global health. Nat. Nanotechnol. 16, 1–14 (2021).
Saunders, K. O. et al. Targeted selection of HIV-specific antibody mutations by engineering B cell maturation. Science 366, eaay7199 (2019).
Kanekiyo, M. et al. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature 499, 102–106 (2013).
Yassine, H. M. et al. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat. Med. 21, 1065–1070 (2015). This study demonstrates that HA stem immunogen displayed on self-assembling nanoparticles induces stem-specific antibodies and protects against diverse viral challenges in animal models.
Impagliazzo, A. et al. A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science 349, 1301–1306 (2015).
He, D. & Marles-Wright, J. Ferritin family proteins and their use in bionanotechnology. New Biotechnol. 32, 651–657 (2015).
Kanekiyo, M. et al. Rational design of an Epstein–Barr virus vaccine targeting the receptor-binding site. Cell 162, 1090–1100 (2015).
Kanekiyo, M. et al. Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses. Nat. Immunol. 20, 362–372 (2019).
Jardine, J. et al. Rational HIV immunogen design to target specific germline B cell receptors. Science 340, 711–716 (2013).
Sanders, R. W. & Moore, J. P. Native-like Env trimers as a platform for HIV-1 vaccine design. Immunol. Rev. 275, 161–182 (2017).
Jardine, J. G. et al. Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen. Science 349, 156–161 (2015). This work demonstrates that HIV immunogen eOD-GT8 binds with VRC01 bnAB precursor germline B cells at the CD4 binding site to prime bnAb response.
Saunders, K. O. et al. Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses. Nature 594, 553–559 (2021).
Cohen, A. A. et al. Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice. Science 371, 735–741 (2021).
Gordon, D. M. et al. Safety, immunogenicity, and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein-hepatitis B surface antigen subunit vaccine. J. Infect. Dis. 171, 1576–1585 (1995).
RTS,S Clinical Trials Partnership Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 386, 31–45 (2015).
Datoo, M. S. et al. Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial. Lancet 403, 533–544 (2024).
Kraft, J. C. et al. Antigen- and scaffold-specific antibody responses to protein nanoparticle immunogens. Cell Rep. Med. 3, 100780 (2022).
Houser, K. V. et al. Safety and immunogenicity of a ferritin nanoparticle H2 influenza vaccine in healthy adults: a phase 1 trial. Nat. Med. 28, 383–391 (2022).
Widge, A. T. et al. An influenza hemagglutinin stem nanoparticle vaccine induces cross-group 1 neutralizing antibodies in healthy adults. Sci. Transl. Med. 15, eade4790 (2023).
Correia, B. E. et al. Proof of principle for epitope-focused vaccine design. Nature 507, 201–206 (2014).
Wang, T. T. et al. Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes. Proc. Natl Acad. Sci. USA 107, 18979–18984 (2010).
Tzarum, N., Wilson, I. A. & Law, M. The neutralizing face of hepatitis C virus E2 envelope glycoprotein. Front. Immunol. 9, 1315 (2018).
Jelínková, L. et al. A vaccine targeting the L9 epitope of the malaria circumsporozoite protein confers protection from blood-stage infection in a mouse challenge model. NPJ Vaccines 7, 34 (2022).
Wang, S. et al. A novel RBD-protein/peptide vaccine elicits broadly neutralizing antibodies and protects mice and macaques against SARS-CoV-2. Emerg. Microbes Infect. 11, 2724–2734 (2022).
Zhao, F., Zai, X., Zhang, Z., Xu, J. & Chen, W. Challenges and developments in universal vaccine design against SARS-CoV-2 variants. NPJ Vaccines 7, 167 (2022).
Wang, Q. et al. Immunodominant SARS coronavirus epitopes in humans elicited both enhancing and neutralizing effects on infection in non-human primates. ACS Infect. Dis. 2, 361–376 (2016).
Mosmann, T. R., McMichael, A. J., LeVert, A., McCauley, J. W. & Almond, J. W. Opportunities and challenges for T cell-based influenza vaccines. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-024-01030-8 (2024).
Nathan, A. et al. Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses. Cell 184, 4401–4413.e10 (2021).
Arieta, C. M. et al. The T-cell-directed vaccine BNT162b4 encoding conserved non-spike antigens protects animals from severe SARS-CoV-2 infection. Cell 186, 2392–2409.e21 (2023).
Tai, W. et al. An mRNA-based T-cell-inducing antigen strengthens COVID-19 vaccine against SARS-CoV-2 variants. Nat. Commun. 14, 2962 (2023).
Carter, B. et al. A pan-variant mRNA-LNP T cell vaccine protects HLA transgenic mice from mortality after infection with SARS-CoV-2 Beta. Front. Immunol. 14, 1135815 (2023).
Dasari, V. et al. Lymph node targeted multi-epitope subunit vaccine promotes effective immunity to EBV in HLA-expressing mice. Nat. Commun. 14, 4371 (2023).
Deeks, S. G. & Walker, B. D. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27, 406–416 (2007).
Moyo, N. et al. Efficient induction of T cells against conserved HIV-1 regions by mosaic vaccines delivered as self-amplifying mRNA. Mol. Ther. Methods Clin. Dev. 12, 32–46 (2019).
Hamley, I. W. Peptides for vaccine development. ACS Appl. Bio Mater. 5, 905–944 (2022).
Chaudhary, N., Weissman, D. & Whitehead, K. A. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat. Rev. Drug Discov. 20, 817–838 (2021).
Bloom, K., van den Berg, F. & Arbuthnot, P. Self-amplifying RNA vaccines for infectious diseases. Gene Ther. 28, 117–129 (2021).
Niu, D., Wu, Y. & Lian, J. Circular RNA vaccine in disease prevention and treatment. Signal. Transduct. Target. Ther. 8, 341 (2023).
Tregoningo, J. S. & Kinnear, E. Using plasmids as DNA vaccines for infectious diseases. Microbiol. Spectr. 10.1128/microbiolspec.plas-0028–2014 (2014).
Cunliffe, R. F. et al. Optimizing a linear ‘Doggybone’ DNA vaccine for influenza virus through the incorporation of DNA targeting sequences and neuraminidase antigen. Discov. Immunol. 3, kyad030 (2024).
Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020).
Walsh, E. E. et al. Safety and immunogenicity of two RNA-based covid-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450 (2020).
Dai, L. & Gao, G. F. Viral targets for vaccines against COVID-19. Nat. Rev. Immunol. 21, 73–82 (2021).
Li, B. et al. Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-023-01082-6 (2023).
Zhang, P. et al. A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques. Nat. Med. 27, 2234–2245 (2021).
Mu, Z. et al. mRNA-encoded HIV-1 Env trimer ferritin nanoparticles induce monoclonal antibodies that neutralize heterologous HIV-1 isolates in mice. Cell Rep. 38, 110514 (2022).
Hoffmann, M. A. G. et al. ESCRT recruitment to SARS-CoV-2 spike induces virus-like particles that improve mRNA vaccines. Cell 186, 2380–2391.e9 (2023). This study utilizes mRNA encoding self-assembling enveloped VLPs that generate robust immune responses in a single injection.
Freyn, A. W. et al. An mpox virus mRNA-lipid nanoparticle vaccine confers protection against lethal orthopoxviral challenge. Sci. Transl. Med. 15, eadg3540 (2024).
Arevalo, C. P. et al. A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes. Science 378, 899–904 (2022).
Martinez, D. R. et al. Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice. Science 373, 991–998 (2021).
Stewart-Jones, G. B. E. et al. Domain-based mRNA vaccines encoding spike protein N-terminal and receptor binding domains confer protection against SARS-CoV-2. Sci. Transl. Med. 15, eadf4100 (2024). This study demonstrates that mRNA vaccines encoding the N-terminal ___domain linked to the RBD of the SARS-CoV-2 spike protein provide comparable or superior protection to those encoding the full-length spike protein. Additionally, these ___domain-based vaccines exhibit better stability at refrigeration temperatures, making them more suitable for global distribution.
Yassini, P. et al. Interim analysis of a phase 1 randomized clinical trial on the safety and immunogenicity of the mRNA-1283 SARS-CoV-2 vaccine in adults. Hum. Vaccines Immunother. 19, 2190690 (2023).
Vostrosablin, N. et al. mRNAid, an open-source platform for therapeutic mRNA design and optimization strategies. NAR Genom. Bioinform. 6, lqae028 (2024).
Li, S. et al. CodonBERT large language models for mRNA design and optimization. Genome Res. 34, 1027–1035 (2024).
Zhang, H. et al. Algorithm for optimized mRNA design improves stability and immunogenicity. Nature 621, 396–403 (2023).
Leppek, K. et al. Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics. Nat. Commun. 13, 1536 (2022).
Freyn, A. W. et al. Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice. Mol. Ther. Methods Clin. Dev. 22, 84–95 (2021).
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).
Huysmans, H. et al. Expression kinetics and innate immune response after electroporation and LNP-mediated delivery of a self-amplifying mRNA in the skin. Mol. Ther. Nucleic Acids 17, 867–878 (2019).
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).
Qu, L. et al. Circular RNA vaccines against SARS-CoV-2 and emerging variants. Cell 185, 1728–1744.e16 (2022).
Wesselhoeft, R. A. et al. RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Mol. Cell 74, 508–520.e4 (2019).
Aditham, A. et al. Chemically modified mocRNAs for highly efficient protein expression in mammalian cells. ACS Chem. Biol. 17, 3352–3366 (2022).
Chen, R. et al. Engineering circular RNA for enhanced protein production. Nat. Biotechnol. 41, 262–272 (2023).
Chen, H. et al. Branched chemically modified poly(A) tails enhance the translation capacity of mRNA. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02174-7 (2024).
Khobragade, A. et al. Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3, randomised, double-blind, placebo-controlled study in India. Lancet 399, 1313–1321 (2022).
Kobiyama, K. & Ishii, K. J. Making innate sense of mRNA vaccine adjuvanticity. Nat. Immunol. 23, 474–476 (2022).
Kawasaki, T., Kawai, T. & Akira, S. Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity. Immunol. Rev. 243, 61–73 (2011).
Liddicoat, B. J. et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120 (2015).
Hornung, V. et al. 5’-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006).
Li, C. et al. Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine. Nat. Immunol. 23, 543–555 (2022).
Tahtinen, S. et al. IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines. Nat. Immunol. 23, 532–542 (2022). This study demonstrates that the ionizable lipid component of mRNA vaccines drives IL-1 pathway activation, TLR signalling and cytokine release, with these effects being more pronounced in human leukocytes than in their murine counterparts.
Dinarello, C. A. Cytokines as endogenous pyrogens. J. Infect. Dis. 179, S294–S304 (1999).
Rathinam, V. A. K., Vanaja, S. K. & Fitzgerald, K. A. Regulation of inflammasome signaling. Nat. Immunol. 13, 333–342 (2012).
Chan, A. H. & Schroder, K. Inflammasome signaling and regulation of interleukin-1 family cytokines. J. Exp. Med. 217, e20190314 (2019).
Karikó, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005).
Karikó, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 16, 1833–1840 (2008).
Oberli, M. A. et al. Lipid nanoparticle assisted mRNA delivery for potent cancer immunotherapy. Nano Lett. 17, 1326–1335 (2017).
Wang, Z. et al. Reducing cell intrinsic immunity to mRNA vaccine alters adaptive immune responses in mice. Mol. Ther. Nucleic Acids 34, 102045 (2023).
Gebre, M. S. et al. Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine. Nature 601, 410–414 (2022).
Mulroney, T. E. et al. N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting. Nature 625, 189–194 (2024).
Klinman, D. M., Yamshchikov, G. & Ishigatsubo, Y. Contribution of CpG motifs to the immunogenicity of DNA vaccines. J. Immunol. 158, 3635–3639 (1997).
Reyes-Sandoval, A. & Ertl, H. C. J. CpG methylation of a plasmid vector results in extended transgene product expression by circumventing induction of immune responses. Mol. Ther. 9, 249–261 (2004).
Mitsui, M. et al. Effect of the content of unmethylated CpG dinucleotides in plasmid DNA on the sustainability of transgene expression. J. Gene Med. 11, 435–443 (2009).
Suschak, J. J., Wang, S., Fitzgerald, K. A. & Lu, S. A cGAS-independent STING/IRF7 pathway mediates the immunogenicity of DNA vaccines. J. Immunol. 196, 310–316 (2016).
Suschak, J. J., Wang, S., Fitzgerald, K. A. & Lu, S. Identification of Aim2 as a sensor for DNA vaccines. J. Immunol. 194, 630–636 (2015).
Allen, A. et al. Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model. Cancer Immunol. Immunother. 67, 627–638 (2018).
Suschak, J. J. et al. Nanoplasmid vectors co-expressing innate immune agonists enhance DNA vaccines for Venezuelan equine encephalitis virus and Ebola virus. Mol. Ther. Methods Clin. Dev. 17, 810–821 (2020).
Didierlaurent, A. M. et al. Enhancement of adaptive immunity by the human vaccine adjuvant AS01 depends on activated dendritic cells. J. Immunol. 193, 1920–1930 (2014).
Calabro, S. et al. Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes. Vaccine 29, 1812–1823 (2011).
Liang, F. et al. Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake. Sci. Transl. Med. 9, eaal2094 (2017).
Moyer, T. J. et al. Engineered immunogen binding to alum adjuvant enhances humoral immunity. Nat. Med. 26, 430–440 (2020).
He, P., Zou, Y. & Hu, Z. Advances in aluminum hydroxide-based adjuvant research and its mechanism. Hum. Vaccines Immunother. 11, 477–488 (2015).
Moyer, T. J., Zmolek, A. C. & Irvine, D. J. Beyond antigens and adjuvants: formulating future vaccines. J. Clin. Investig. 126, 799–808 (2016).
Reed, S. G., Orr, M. T. & Fox, C. B. Key roles of adjuvants in modern vaccines. Nat. Med. 19, 1597–1608 (2013).
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).
Moody, M. A. et al. Toll-like receptor 7/8 (TLR7/8) and TLR9 agonists cooperate to enhance HIV-1 envelope antibody responses in rhesus macaques. J. Virol. 88, 3329–3339 (2014).
Cooper, C. & Mackie, D. Hepatitis B surface antigen-1018 ISS adjuvant-containing vaccine: a review of HEPLISAVTM safety and efficacy. Expert Rev. Vaccines 10, 417–427 (2011).
Hou, B. et al. Selective utilization of toll-like receptor and MyD88 signaling in B cells for enhancement of the antiviral germinal center response. Immunity 34, 375–384 (2011).
Francica, J. R. et al. Analysis of immunoglobulin transcripts and hypermutation following SHIVAD8 infection and protein-plus-adjuvant immunization. Nat. Commun. 6, 6565 (2015).
Stertman, L. et al. The Matrix-MTM adjuvant: a critical component of vaccines for the 21st century. Hum. Vaccines Immunother. 19, 2189885 (2023).
Counoupas, C. et al. Delta inulin-based adjuvants promote the generation of polyfunctional CD4+ T cell responses and protection against Mycobacterium tuberculosis infection. Sci. Rep. 7, 8582 (2017).
Casella, C. R. & Mitchell, T. C. Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant. Cell. Mol. Life Sci. 65, 3231–3240 (2008).
Baay, M., Bollaerts, K. & Verstraeten, T. A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among older adults. Vaccine 36, 4207–4214 (2018).
Miller, E. et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 346, f794 (2013).
Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014).
Ushach, I. et al. Targeting TLR9 agonists to secondary lymphoid organs induces potent immune responses against HBV infection. Mol. Ther. Nucleic Acids 27, 1103–1115 (2022).
Yin, Q. et al. A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2. Nat. Mater. 22, 380–390 (2023).
Mitragotri, S., Burke, P. A. & Langer, R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat. Rev. Drug Discov. 13, 655–672 (2014).
Trevaskis, N. L., Kaminskas, L. M. & Porter, C. J. H. From sewer to saviour — targeting the lymphatic system to promote drug exposure and activity. Nat. Rev. Drug Discov. 14, 781–803 (2015).
Barbier, A. J., Jiang, A. Y., Zhang, P., Wooster, R. & Anderson, D. G. The clinical progress of mRNA vaccines and immunotherapies. Nat. Biotechnol. 40, 840–854 (2022).
Ho, W. et al. Next-generation vaccines: nanoparticle-mediated DNA and mRNA delivery. Adv. Healthc. Mater. 10, 2001812 (2021).
Buschmann, M. D. et al. Nanomaterial delivery systems for mRNA vaccines. Vaccines 9, 65 (2021).
Smith, D. M., Simon, J. K. & Baker, J. R. Jr Applications of nanotechnology for immunology. Nat. Rev. Immunol. 13, 592–605 (2013).
Irvine, D. J., Hanson, M. C., Rakhra, K. & Tokatlian, T. Synthetic nanoparticles for vaccines and immunotherapy. Chem. Rev. 115, 11109–11146 (2015).
Tibbitt, M. W., Dahlman, J. E. & Langer, R. Emerging frontiers in drug delivery. J. Am. Chem. Soc. 138, 704–717 (2016).
Pati, R., Shevtsov, M. & Sonawane, A. Nanoparticle vaccines against infectious diseases. Front. Immunol. 9, 2224 (2018).
Gupta, A., Andresen, J. L., Manan, R. S. & Langer, R. Nucleic acid delivery for therapeutic applications. Adv. Drug. Deliv. Rev. 178, 113834 (2021).
Zhong, R. et al. Hydrogels for RNA delivery. Nat. Mater. 22, 818–831 (2023).
Kirtane, A. R. et al. Nanotechnology approaches for global infectious diseases. Nat. Nanotechnol. 16, 369–384 (2021).
Pauthner, M. et al. Elicitation of robust tier 2 neutralizing antibody responses in nonhuman primates by HIV envelope trimer immunization using optimized approaches. Immunity 46, 1073–1088.e6 (2017).
Di, J. et al. Biodistribution and non-linear gene expression of mRNA LNPs affected by delivery route and particle size. Pharm. Res. 39, 105–114 (2022).
Hassett, K. J. et al. mRNA vaccine trafficking and resulting protein expression after intramuscular administration. Mol. Ther. Nucleic Acids 35, 102083 (2024).
Liang, F. et al. Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques. Mol. Ther. 25, 2635–2647 (2017).
Hassett, K. J. et al. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Mol. Ther. Nucleic Acids 15, 1–11 (2019).
Hope, M. et al. Lipid nanoparticle formulations. WIPO patent WO-2018081480-A1 (2018).
Lu, X., Li, Z., Song, H. & Ying, B. Quadrivalent mRNA vaccines for influenza viruses. WIPO patent WO2023125889A1 (2023).
Zhang, N.-N. et al. A thermostable mRNA vaccine against COVID-19. Cell 182, 1271–1283.e16 (2020).
Rajappan, K. et al. Property-driven design and development of lipids for efficient delivery of siRNA. J. Med. Chem. 63, 12992–13012 (2020).
Lam, K. et al. Unsaturated, trialkyl ionizable lipids are versatile lipid-nanoparticle components for therapeutic and vaccine applications. Adv. Mater. 35, e2209624 (2023).
Gatechompol, S. et al. Safety and immunogenicity of a prefusion non-stabilized spike protein mRNA COVID-19 vaccine: a phase I trial. Nat. Microbiol. 7, 1987–1995 (2022).
Broudic, K. et al. Nonclinical safety evaluation of a novel ionizable lipid for mRNA delivery. Toxicol. Appl. Pharmacol. 451, 116143 (2022).
Kalnin, K. V. et al. Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models. NPJ Vaccines 6, 61 (2021).
DeRosa, F., Karve, S. & Heartlein, M. Stereochemically enriched compositions for delivery of nucleic acids. US patent US20190185435A1 (2019).
Koizumi, M., Onishi, Y., Niwa, T., Tamura, M. & Kasuya, Y. Novel lipid. WIPO patent WO2015005253A1 (2015).
Nussbaum, J. et al. Evaluation of a stabilized RSV pre-fusion F mRNA vaccine: preclinical studies and Phase 1 clinical testing in healthy adults. Vaccine 41, 6488–6501 (2023).
Duncan, R., Clancy, E. K., Lewis, J., Justo De Antueno, R. & Nesbitt R.-L. Recombinant polypeptides for membrane fusion and uses thereof. US patent 10,227,386B2 (2019).
Hervé, C., Laupèze, B., Del Giudice, G., Didierlaurent, A. M. & Da Silva, F. T. The how’s and what’s of vaccine reactogenicity. NPJ Vaccines 4, 39 (2019).
De Lombaerde, E. Combinatorial screening of biscarbamate ionizable lipids identifies a low reactogenicity lipid for lipid nanoparticle mRNA delivery. Adv. Funct. Mater. 34, 2310623 (2024).
Lee, B. et al. Disruptions in endocytic traffic contribute to the activation of the NLRP3 inflammasome. Sci. Signal. 16, eabm7134 (2023).
Thurston, T. L. M., Wandel, M. P., von Muhlinen, N., Foeglein, Á. & Randow, F. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482, 414–418 (2012).
Holm, C. K. et al. Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING. Nat. Immunol. 13, 737–743 (2012).
Alameh, M. G. et al. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. Immunity 54, 2877–2892.e7 (2021). This study demonstrates that LNPs can function as adjuvants by stimulating IL-6 production, thereby enhancing antigen-specific follicular T-helper and germinal centre B cell responses and amplifying immune responses when used with protein subunit vaccines.
Ju, Y. et al. Impact of anti-PEG antibodies induced by SARS-CoV-2 mRNA vaccines. Nat. Rev. Immunol. 23, 135–136 (2023).
Miao, L. et al. Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. Nat. Biotechnol. 37, 1174–1185 (2019).
Zhang, Y. et al. STING agonist-derived LNP-mRNA vaccine enhances protective immunity against SARS-CoV-2. Nano Lett. 23, 2593–2600 (2023).
Han, X. et al. Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines. Nat. Nanotechnol. 18, 1105–1114 (2023).
Yan, J. et al. Nanomaterials-mediated co-stimulation of toll-like receptors and CD40 for antitumor immunity. Adv. Mater. 34, e2207486 (2022).
Kelly, G., Laczka, O. & Gantier, M. Methods for the treatment of inflammation associated with infection. US Patent US11541030B2 (2023).
Tong, A.-J. et al. Nucleotide modifications enable rational design of TLR7-selective ligands by blocking RNase cleavage. J. Exp. Med. 221, e20230341 (2023).
Lan, T. et al. Stabilized immune modulatory RNA compounds as agonists of Toll-like receptors 7 and 8. Proc. Natl Acad. Sci. USA 104, 13750–13755 (2007).
Kandimalla, E. R. et al. Synthesis and immunological activities of novel Toll-like receptor 7 and 8 agonists. Cell. Immunol. 270, 126–134 (2011).
Shirai, S. et al. Lipid nanoparticles potentiate CpG-oligodeoxynucleotide-based vaccine for influenza virus. Front. Immunol. 10, 3018 (2019).
Kastenmüller, W., Kastenmüller, K., Kurts, C. & Seder, R. A. Dendritic cell-targeted vaccines — hope or hype? Nat. Rev. Immunol. 14, 705–711 (2014).
Tang, X. et al. Simultaneous dendritic cells targeting and effective endosomal escape enhance sialic acid-modified mRNA vaccine efficacy and reduce side effects. J. Control. Release 364, 529–545 (2023).
Wan, J. et al. Circular RNA vaccines with long-term lymph node-targeting delivery stability after lyophilization induce potent and persistent immune responses. mBio 15, e0177523 (2024).
Talukder, P., Chahal, J., Huang, J. & Ruping, K. Carriers for efficient nucleic acid delivery. WIPO patent WO2021207020A1 (2021).
Künzli, M. et al. Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells. Sci. Immunol. 7, eadd3075 (2022).
Ndeupen, S. et al. The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory. iScience 24, 103479 (2021).
Wibowo, D. et al. Polymeric nanoparticle vaccines to combat emerging and pandemic threats. Biomaterials 268, 120597 (2021).
Vogel, A. B. et al. Self-amplifying RNA vaccines give equivalent protection against influenza to mRNA vaccines but at much lower doses. Mol. Ther. 26, 446–455 (2018).
Blakney, A. K., Yilmaz, G., McKay, P. F., Becer, C. R. & Shattock, R. J. One size does not fit all: the effect of chain length and charge density of poly(ethylene imine) based copolymers on delivery of pDNA, mRNA, and RepRNA polyplexes. Biomacromolecules 19, 2870–2879 (2018).
Li, M. et al. Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways. J. Control. Release 228, 9–19 (2016).
Blakney, A. K. et al. Big is beautiful: enhanced saRNA delivery and immunogenicity by a higher molecular weight, bioreducible, cationic polymer. ACS Nano 14, 5711–5727 (2020).
Chahal, J. S. et al. Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Proc. Natl Acad. Sci. USA 113, E4133–42 (2016).
Chahal, J. S. et al. An RNA nanoparticle vaccine against Zika virus elicits antibody and CD8+ T cell responses in a mouse model. Sci. Rep. 7, 252 (2017).
Zhou, J. et al. Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery. Nat. Mater. 11, 82–90 (2012).
Suberi, A. et al. Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination. Sci. Transl. Med. 15, eabq0603 (2024).
Amaya, L. et al. Circular RNA vaccine induces potent T cell responses. Proc. Natl Acad. Sci. USA 120, e2302191120 (2023).
Haabeth, O. A. W. et al. An mRNA SARS-CoV-2 vaccine employing charge-altering releasable transporters with a TLR-9 agonist induces neutralizing antibodies and T cell memory. ACS Cent. Sci. 7, 1191–1204 (2021).
Kasturi, S. P. et al. Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470, 543–547 (2011).
Kasturi, S. P. et al. 3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope–specific plasma cells and humoral immunity in nonhuman primates. Sci. Immunol. 5, eabb1025 (2020). This study demonstrates that 3M-052 enhances the response to an HIV-1 Env protein vaccine in rhesus macaques, leading to long-lasting antibody responses detectable a year later. This effect is attributed to the ability of 3M-052 to sustain long-lived plasma cell responses.
Dhakal, S. et al. Biodegradable nanoparticle delivery of inactivated swine influenza virus vaccine provides heterologous cell-mediated immune response in pigs. J. Control. Release 247, 194–205 (2017).
Zhang, Y. et al. Rationally designed self-assembling nanoparticles to overcome mucus and epithelium transport barriers for oral vaccines against Helicobacter pylori. Adv. Funct. Mater. 28, 1802675 (2018).
Lei, H. et al. Cationic nanocarriers as potent adjuvants for recombinant S-RBD vaccine of SARS-CoV-2. Signal Transduct. Target. Ther. 5, 291 (2020).
Wilson, D. S. et al. Antigens reversibly conjugated to a polymeric glyco-adjuvant induce protective humoral and cellular immunity. Nat. Mater. 18, 175–185 (2019).
Gray, L. T. et al. Generation of potent cellular and humoral immunity against SARS-CoV-2 antigens via conjugation to a polymeric glyco-adjuvant. Biomaterials 278, 121159 (2021).
Liong, C. S. et al. Enhanced humoral immune response by high density TLR agonist presentation on hyperbranched polymers. Adv. Ther. 4, 2000081 (2021).
Atalis, A. et al. Nanoparticle-delivered TLR4 and RIG-I agonists enhance immune response to SARS-CoV-2 subunit vaccine. J. Control. Release 347, 476–488 (2022).
Knight, F. C. et al. Mucosal immunization with a pH-responsive nanoparticle vaccine induces protective CD8+ lung-resident memory T cells. ACS Nano 13, 10939–10960 (2019).
Deng, Y. et al. Rational development of a polysaccharide–protein-conjugated nanoparticle vaccine against SARS-CoV-2 variants and Streptococcus pneumoniae. Adv. Mater. 34, e2200443 (2022).
Veneziano, R. et al. Role of nanoscale antigen organization on B-cell activation probed using DNA origami. Nat. Nanotechnol. 15, 716–723 (2020).
Kato, Y. et al. Multifaceted effects of antigen valency on B cell response composition and differentiation in vivo. Immunity 53, 548–563.e8 (2020).
Martinez-Murillo, P. et al. Particulate array of well-ordered HIV clade C Env trimers elicits neutralizing antibodies that display a unique V2 cap approach. Immunity 46, 804–817.e7 (2017).
Fries, L. F., Smith, G. E. & Glenn, G. M. A recombinant viruslike particle influenza A (H7N9) vaccine. N. Engl. J. Med. 369, 2564–2566 (2013).
Liu, Y. V. et al. Recombinant virus-like particles elicit protective immunity against avian influenza A(H7N9) virus infection in ferrets. Vaccine 33, 2152–2158 (2015).
Krammer, F. & Palese, P. Advances in the development of influenza virus vaccines. Nat. Rev. Drug Discov. 14, 167–182 (2015).
Ward, B. J. et al. Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19. Nat. Med. 27, 1071–1078 (2021).
Huang, W.-C. et al. A malaria vaccine adjuvant based on recombinant antigen binding to liposomes. Nat. Nanotechnol. 13, 1174–1181 (2018).
Wang, Z. et al. Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding ___domain as an inhalable COVID-19 vaccine. Nat. Biomed. Eng. 6, 791–805 (2022).
Popowski, K. D. et al. Inhalable dry powder mRNA vaccines based on extracellular vesicles. Matter 5, 2960–2974 (2022).
Weyant, K. B. et al. A modular vaccine platform enabled by decoration of bacterial outer membrane vesicles with biotinylated antigens. Nat. Commun. 14, 464 (2023).
Fazli, S. et al. Contralateral second dose improves antibody responses to a two-dose mRNA vaccination regimen. J. Clin. Investig. 34, e176411 (2024).
Wang, X. et al. Multiplexed CRISPR/CAS9‐mediated engineering of pre‐clinical mouse models bearing native human B cell receptors. EMBO J. 40, e105926 (2020).
Brehm, M. A., Wiles, M. V., Greiner, D. L. & Shultz, L. D. Generation of improved humanized mouse models for human infectious diseases. J. Immunol. Methods 410, 3–17 (2014).
Higbee, R. G. et al. An immunologic model for rapid vaccine assessment — a clinical trial in a test tube. Altern. Lab. Anim. 37, 19–27 (2009).
Rainho-Tomko, J. N. et al. Immunogenicity and protective efficacy of RSV G central conserved ___domain vaccine with a prefusion nanoparticle. NPJ Vaccines 7, 74 (2022).
Massare, M. J. et al. Combination respiratory vaccine containing recombinant SARS-CoV-2 spike and quadrivalent seasonal influenza hemagglutinin nanoparticles with matrix-M adjuvant. Preprint at bioRxiv https://doi.org/10.1101/2021.05.05.442782 (2021).
Prompetchara, E. et al. Immunogenicity and protective efficacy of SARS-CoV-2 mRNA vaccine encoding secreted non-stabilized spike in female mice. Nat. Commun. 14, 2309 (2023).
Song, J. Y. et al. Safety and immunogenicity of a SARS-CoV-2 recombinant protein nanoparticle vaccine (GBP510) adjuvanted with AS03: a randomised, placebo-controlled, observer-blinded phase 1/2 trial. EClinicalMedicine 51, 101569 (2022).
Saraf, A. et al. An Omicron-specific, self-amplifying mRNA booster vaccine for COVID-19: a phase 2/3 randomized trial. Nat. Med. 30, 1363–1372 (2024).
Tian, J.-H. et al. SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice. Nat. Commun. 12, 372 (2021).
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).
Ward, B. J., Séguin, A., Couillard, J., Trépanier, S. & Landry, N. Phase III: randomized observer-blind trial to evaluate lot-to-lot consistency of a new plant-derived quadrivalent virus like particle influenza vaccine in adults 18–49 years of age. Vaccine 39, 1528–1533 (2021).
Shinde, V. et al. Comparison of the safety and immunogenicity of a novel Matrix-M-adjuvanted nanoparticle influenza vaccine with a quadrivalent seasonal influenza vaccine in older adults: a phase 3 randomised controlled trial. Lancet Infect. Dis. 22, 73–84 (2022).
Treanor, J. et al. A phase 2 study of the bivalent VLP norovirus vaccine candidate in older adults; impact of MPL adjuvant or a second dose. Vaccine 38, 5842–5850 (2020).
Chen, G. L. et al. Effect of a chikungunya virus–like particle vaccine on safety and tolerability outcomes: a randomized clinical trial. JAMA 323, 1369–1377 (2020).
Bennett, S. R. et al. Safety and immunogenicity of PXVX0317, an aluminium hydroxide-adjuvanted chikungunya virus-like particle vaccine: a randomised, double-blind, parallel-group, phase 2 trial. Lancet Infect. Dis. 22, 1343–1355 (2022).
Datoo, M. S. et al. Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years’ follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial. Lancet Infect. Dis. 22, 1728–1736 (2022).
Lewnard, J. A., Fries, L. F., Cho, I., Chen, J. & Laxminarayan, R. Prevention of antimicrobial prescribing among infants following maternal vaccination against respiratory syncytial virus. Proc. Natl Acad. Sci. USA 119, e2112410119 (2022).
Falloon, J. et al. An adjuvanted, postfusion F protein–based vaccine did not prevent respiratory syncytial virus illness in older adults. J. Infect. Dis. 216, 1362–1370 (2017).
Fly, J. H., Eiland, L. S. & Stultz, J. S. Nirsevimab: expansion of respiratory syncytial virus prevention options in neonates, infants, and at-risk young children. Ann. Pharmacother. https://doi.org/10.1177/10600280241243357 (2024).
Bollman, B. et al. An optimized messenger RNA vaccine candidate protects non-human primates from Zika virus infection. NPJ Vaccines 8, 58 (2023).
Plotkin, S. A. Updates on immunologic correlates of vaccine-induced protection. Vaccine 38, 2250–2257 (2020).
Boes, M. Role of natural and immune IgM antibodies in immune responses. Mol. Immunol. 37, 1141–1149 (2000).
Burton, D. R. Antibodies, viruses and vaccines. Nat. Rev. Immunol. 2, 706–713 (2002).
Corthésy, B. Multi-faceted functions of secretory IgA at mucosal surfaces. Front. Immunol. 4, 185 (2013).
Dogan, I. et al. Multiple layers of B cell memory with different effector functions. Nat. Immunol. 10, 1292–1299 (2009).
Heesters, B. A., Myers, R. C. & Carroll, M. C. Follicular dendritic cells: dynamic antigen libraries. Nat. Rev. Immunol. 14, 495–504 (2014).
Crotty, S. T. Follicular helper cell biology: a decade of discovery and diseases. Immunity 50, 1132–1148 (2019).
Pape, K. A., Catron, D. M., Itano, A. A. & Jenkins, M. K. The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity 26, 491–502 (2007).
De Silva, N. S. & Klein, U. Dynamics of B cells in germinal centres. Nat. Rev. Immunol. 15, 137–148 (2015).
Klein, F. et al. Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell 153, 126–138 (2013).
Turner, J. S. et al. SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Nature 596, 109–113 (2021). This study demonstrates that mRNA vaccines, such as BNT162b2, induce a strong but transient plasmablast response and a sustained germinal centre B cell response in lymph nodes, contributing to long-lasting humoral immunity. Additionally, cross-reactive B cell clones exhibit higher levels of somatic hypermutation, suggesting a memory B cell origin.
Sallusto, F., Lanzavecchia, A., Araki, K. & Ahmed, R. From vaccines to memory and back. Immunity 33, 451–463 (2010).
Akkaya, M., Kwak, K. & Pierce, S. K. B cell memory: building two walls of protection against pathogens. Nat. Rev. Immunol. 20, 229–238 (2020).
Batista, F. D. & Harwood, N. E. The who, how and where of antigen presentation to B cells. Nat. Rev. Immunol. 9, 15–27 (2009).
Akondy, R. S. et al. The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. J. Immunol. 183, 7919–7930 (2009).
Arunachalam, P. S. et al. T cell-inducing vaccine durably prevents mucosal SHIV infection even with lower neutralizing antibody titers. Nat. Med. 26, 932–940 (2020). This study shows that vaccines inducing a strong antigen-specific CD8+ memory T cell response lower the threshold of neutralizing antibodies to elicit protection against the infection, indicating a potential synergy between TRM cells and antibody responses.
Miller, J. D. et al. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity 28, 710–722 (2008).
Eickhoff, S. et al. Robust anti-viral immunity requires multiple distinct T cell-dendritic cell interactions. Cell 162, 1322–1337 (2015).
Qi, H., Kastenmüller, W. & Germain, R. N. Spatiotemporal basis of innate and adaptive immunity in secondary lymphoid tissue. Annu. Rev. Cell Dev. Biol. 30, 141–167 (2014).
Chang, J. T., Wherry, E. J. & Goldrath, A. W. Molecular regulation of effector and memory T cell differentiation. Nat. Immunol. 15, 1104–1115 (2014).
Gerlach, C. et al. One naive T cell, multiple fates in CD8+ T cell differentiation. J. Exp. Med. 207, 1235–1246 (2010).
Stemberger, C. et al. A single naive CD8+ T cell precursor can develop into diverse effector and memory subsets. Immunity 27, 985–997 (2007).
Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524–530 (2009).
Schenkel, J. M. et al. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).
Kaech, S. M., Wherry, E. J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nat. Rev. Immunol. 2, 251–262 (2002).
Wu, T. et al. Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J. Leukoc. Biol. 95, 215–224 (2014).
Pizzolla, A. et al. Resident memory CD8+ T cells in the upper respiratory tract prevent pulmonary influenza virus infection. Sci. Immunol. 2, eaam6970 (2017).
Zhou, L., Chong, M. M. W. & Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).
Bournazos, S., Gupta, A. & Ravetch, J. V. The role of IgG Fc receptors in antibody-dependent enhancement. Nat. Rev. Immunol. 20, 633–643 (2020).
Lee, S. K. et al. B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J. Exp. Med. 208, 1377–1388 (2011).
Mantovani, A., Dinarello, C. A., Molgora, M. & Garlanda, C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50, 778–795 (2019).
Saper, C. B., Romanovsky, A. A. & Scammell, T. E. Neural circuitry engaged by prostaglandins during the sickness syndrome. Nat. Neurosci. 15, 1088–1095 (2012).
Talbot, S., Foster, S. L. & Woolf, C. J. Neuroimmunity: physiology and pathology. Annu. Rev. Immunol. 34, 421–447 (2016).
Sobolev, O. et al. Adjuvanted influenza-H1N1 vaccination reveals lymphoid signatures of age-dependent early responses and of clinical adverse events. Nat. Immunol. 17, 204–213 (2016).
Iwasaki, A. & Yang, Y. The potential danger of suboptimal antibody responses in COVID-19. Nat. Rev. Immunol. 20, 339–341 (2020).
Arvin, A. M. et al. A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature 584, 353–363 (2020).
Katzelnick, L. C. et al. Antibody-dependent enhancement of severe dengue disease in humans. Science 358, 929–932 (2017).
Houser, K. V. et al. Enhanced inflammation in New Zealand white rabbits when MERS-CoV reinfection occurs in the absence of neutralizing antibody. PLoS Pathog. 13, e1006565 (2017).
Chin, J., Magoffin, R. L., Shearer, L. A. N. N., Schieble, J. H. & Lennette, E. H. Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population1. Am. J. Epidemiol. 89, 449–463 (1969).
Ruckwardt, T. J., Morabito, K. M. & Graham, B. S. Immunological lessons from respiratory syncytial virus vaccine development. Immunity 51, 429–442 (2019).
Graham, B. S. et al. Priming immunization determines T helper cytokine mRNA expression patterns in lungs of mice challenged with respiratory syncytial virus. J. Immunol. 151, 2032–2040 (1993).
Openshaw, P. J. M., Chiu, C., Culley, F. J. & Johansson, C. Protective and harmful immunity to RSV infection. Annu. Rev. Immunol. 35, 501–532 (2017).
Mabrouk, M. T. et al. Lyophilized, thermostable Spike or RBD immunogenic liposomes induce protective immunity against SARS-CoV-2 in mice. Sci. Adv. 7, eabj1476 (2023).
Muramatsu, H. et al. Lyophilization provides long-term stability for a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine. Mol. Ther. 30, 1941–1951 (2022).
Ai, L. et al. Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2. Cell Discov. 9, 9 (2023).
Ye, T. et al. Inhaled SARS-CoV-2 vaccine for single-dose dry powder aerosol immunization. Nature 624, 630–638 (2023). This study reports inhaled dry powder vaccine formulation that induces respiratory mucosal immunity, eliminating the need for cold storage and needles.
vander Straeten, A. et al. A microneedle vaccine printer for thermostable COVID-19 mRNA vaccines. Nat. Biotechnol. 42, 510–517 (2023).
Acknowledgements
This work was supported by Sanofi (formerly Translate Bio), the NIH (grant nos. R61 AI161805), and the Marble Center for Cancer Nanomedicine and Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
D.G.A. receives research funding from Sanofi/Translate Bio and is a founder of oRNA Tx. For a list of entities with which R.L. is or has recently been involved — compensated or uncompensated — see the Supplementary Information section. The other authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Drug Discovery thanks Mansoor Amiji, Yizhou Dong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Glossary
- Adjuvants
-
Vaccine additives that activate pattern recognition receptors to boost cytokine release and recruit immune cells, enhancing the antigen-specific immune response.
- Germinal centre
-
Specialized compartment in lymphoid organs where B cells rapidly proliferate, mutate and mature to produce high-affinity antibodies and memory cells.
- Ionizable lipid
-
A lipid that remains neutral at physiological pH but gets protonated at low pH to facilitate endosomal escape; it is commonly used in lipid nanoparticles for RNA delivery.
- Isotype switching
-
The process by which antigen-experienced B cells switch to produce different classes of antibodies, such as from IgM to IgG, to adapt to various stages of the immune response.
- Lipid nanoparticles
-
(LNPs). Formulations that deliver nucleic acid-based therapeutics into cells, providing stability and protection for efficient delivery and enhanced cytoplasmic release.
- MHC-I
-
The major histocompatibility complex class I (MHC-I) is a protein complex encoded by the HLA-A, HLA-B and HLA-C genes in humans. It consists of β2-microglobulin and an α-chain, and it is expressed on the surface of all nucleated cells. MHC-I plays a crucial role in presenting peptides, which are synthesized intracellularly, to CD8+ T cells.
- MHC-II
-
The major histocompatibility complex class II (MHC-II) is a protein complex encoded by the HLA-DR, HLA-DP and HLA-DQ genes in humans. It consists of an α-chain and a β-chain, and it is expressed on the surface of specialized antigen-presenting cells. MHC-II is responsible for presenting extracellular peptides to CD4+ T cells.
- Neutralizing antibody
-
The antibody that binds to a pathogen to prevent it from entering or damaging the host cells.
- Pattern recognition receptors
-
(PRRs). A group of either membrane-bound or cytoplasmic proteins in innate immune cells that detect (1) specific patterns in microbial components, such as bacterial carbohydrates, nucleic acids, peptides, peptidoglycans and lipoproteins, or (2) molecules released by damaged cells to initiate an immune response.
- Reactogenicity
-
Adverse reactions, such as pain, fever or swelling, occurring locally or systemically after vaccine administration.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Gupta, A., Rudra, A., Reed, K. et al. Advanced technologies for the development of infectious disease vaccines. Nat Rev Drug Discov 23, 914–938 (2024). https://doi.org/10.1038/s41573-024-01041-z
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41573-024-01041-z
