BackgroundMonoclonal antibodies (mAbs) are an increasingly essential class of medicines across many disease areas. In the human body, there are five antibody isotypes, each with potential therapeutic benefits for different disease indications. However, 97% of all clinically approved mAbs are produced as the IgG isotype, largely due to challenges associated with recombinantly producing non-IgG isotypes like IgM or IgA, which have additional N-linked glycan sites and can present as multivalent oligomers. One potential way to circumvent this challenge is to express mAbs in situ using mRNA encapsulated in lipid nanoparticles (LNP), bypassing the need for recombinant protein production.ObjectiveHere, we demonstrate the feasibility of expressing a mAb as both IgG and IgA in non-human primates (NHPs) using mRNA-LNPs.MethodsWe express ePGDM1400v9, a broadly neutralizing mAb targeting human immunodeficiency virus (HIV), in both IgG1 and IgA2 formats by infusing NHPs with LNPs containing the appropriate mRNAs.ResultsThough IgA2 expression levels were low, both formats were detectable in serum within one day of LNP infusion in all NHPs, and both were detectable in mucosal secretions of most animals. Importantly, serum mRNA-produced IgG1 and IgA2 retained HIV-neutralizing function. Furthermore, mass spectrometry analysis confirmed that mAbs of either isotype produced in situ exhibited glycosylation patterns highly similar to that of native antibody, which is likely to confer therapeutic advantages.ConclusionAltogether, this work demonstrates that mRNA-LNPs can be used to express native like mAbs of non-IgG isotypes in primates at detectable levels and enables further development and optimization of non-IgG mAb constructs.

Breast milk confers infants with immunity to a multitude of pathogens reflective of prior maternal infections and vaccinations. However, in outbreak situations where infants may be vulnerable to lethal infections due to gaps in the maternal immune repertoire, a case can be made for supplementing breast milk with one or more pathogen-specific monoclonal antibodies (mAbs) with known prophylactic or therapeutic activity. As oral delivery of recombinant IgG and IgA mAbs to infants has proven challenging, we investigated the use of mRNA-lipid nanoparticle (LNP) technology to stimulate pathogen-specific mAbs in milk. mRNA encoding the Vibrio cholerae O1 specific mAb, ZAC-3, as a human IgG1 or dimeric IgA2, was encapsulated in lipid nanoparticles (LNP) and administered parenterally to lactating and non-lactating female mice. A single intravenous administration of mRNA-LNPs resulted in high and sustained expression of functional ZAC-3 IgG1 in the blood and breast milk of lactating dams. ZAC-3 IgA2 levels were lower and more transient. ZAC-3 IgG1 (but not IgA2) was also detected in the serum of suckling pups at levels proportional to those in the mothers, demonstrating successful transfer of functional antibodies to newborns. Levels of ZAC-3 IgG1 and IgA2 were not sufficient to limit intestinal colonization of V. cholerae O1 when pups were separated from dams following intragastric challenge; however, a significant reduction in bacterial burden was observed when challenged pups remained with dams for continuous breastfeeding. Our findings highlight the potential of mRNA-based mAb platforms in the maternal-newborn context, while acknowledging the need for optimized antibody isotypes, dosing, and tissue-specific delivery to improve mucosal immunity.

Outer surface protein A (OspA) is a ~30 kDa lipoprotein displayed on the surface of Borrelia burgdorferi sensu lato, the etiological agent of Lyme disease. Here we report on the preclinical evaluation of OspA-encoding nucleoside-modified mRNA lipid nanoparticle (OspA mRNA-LNP) vaccines for the prevention of Lyme disease. Crystallographic and binding studies using a panel of transmission-blocking antibodies confirmed that the mRNA-encoded OspA serotype 1 (ST1) expressed in mammalian cells assumes its native structure and retains known protective epitopes. Immunization of mice with OspA ST1 mRNA-LNP elicited functional serum antibodies that promoted spirochete agglutination and complement-dependent borreliacidal activity in vitro. We also examined the impact of combining ST1 OspA mRNA with OspA STs 2-7, which are associated with predominant Borrelia genospecies in Europe (B. garinii, B. afzelii, and B. bavariensis). The additional six STs mRNA did not interfere with ST1 antibody titers and functionality. Finally, mice vaccinated two or three times with different dose levels of OspA ST1 mRNA-LNP or with the heptavalent mRNA vaccine were protected against B. burgdorferi infection in a tick-mediated challenge model. The monovalent and the heptavalent OspA mRNA vaccines (mRNA-1982 and mRNA-1975, respectively) are currently undergoing testing in a Phase 1 clinical trial (NCT05975099).

BACKGROUND:Cell-mediated immunity contributes to durable protection against COVID-19. mRNA-1283 vaccine, encoding the receptor-binding and N-terminal domains of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike protein, elicits higher neutralizing antibody responses than mRNA-1273, which encodes the full-length spike protein. We report T-cell responses following mRNA-1283 vaccination in preclinical and clinical studies. METHODS:For the preclinical evaluation, BALB/c mice received a 2-dose primary series of mRNA-1273 (days 1 and 22), followed by 1 dose of mRNA-1283.222 or mRNA-1273.222 (ancestral + BA.4/BA.5; day 63). C57BL/6 mice received mRNA-1283.815 or mRNA-1273.815 (XBB.1.5; days 1 and 22). T-cell analyses were conducted on spleens from all vaccinated BALB/c and C57BL mice (collected on days 77 and 36, respectively). In the clinical setting, a group of adult (≥18 years) participants in a randomized phase 2 trial (NCT05137236) received 1 dose of mRNA-1283 (ancestral SARS-CoV-2), mRNA-1283.211 (ancestral + beta), mRNA-1283.529 (BA.1), or mRNA-1273 (ancestral), and their SARS-CoV-2 S-protein-specific T-cell responses at days 1 (baseline), 29, 181, and 366 postvaccination were measured. RESULTS:In the mice studies, mRNA-1283 elicited potent S1-directed CD4+ and CD8+ T-cell responses. In the phase 2 study, mRNA-1283 increased S1-specific CD4+ and CD8+ Th1 responses at day 29 postvaccination compared with baseline; responses persisted through day 366 and were similar to mRNA-1273 for all tested strains (ancestral, beta, and BA.1). CONCLUSIONS:In preclinical and clinical studies, mRNA-1283 induced T-cell responses similar to mRNA-1273.

Germline targeting (GT) is a promising strategy to activate rare broadly neutralizing antibody (bnAb)-producing B cells against HIV, but induction of such responses in outbred animals has not been achieved. Using antibody-guided structure-based design, we engineered a GT HIV trimer immunogen, Q23-APEX-GT2, which primes diverse V2-apex bnAb precursors. Q23-APEX-GT2 efficiently activated rare V2-apex-specific B cells in humanized knockin mice and consistently elicited immunofocused antibody responses in outbred rhesus macaques, priming multiple long heavy-chain complementarity-determining region 3 (CDRH3)-loop bnAb-B cell lineages. Monoclonal antibodies isolated from immunized macaques showed broad heterologous HIV trimer recognition and modest cross-neutralization of diverse tier-2 viruses. Cryoelectron microscopy (cryo-EM) structural studies confirmed precise epitope targeting and revealed CDRH3-mediated binding modes that mirrored those of human V2-apex bnAbs. Together, these findings establish proof of principle for priming and early maturation of authentic V2-apex bnAb precursors in outbred macaques and highlight the promise of V2-apex-targeted HIV vaccines.

The ongoing adaptive evolution of Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is characterized by the continued emergence of variants with increased transmissibility and the ability to escape infection- and/or vaccine-induced immunity. This sustained antigenic evolution has necessitated updates to COVID-19 vaccine compositions to better match circulating viral variants. To optimize protection against emerging variants, a reliable means of predicting the immune escape of novel variants is needed to enable at-risk preparation of new vaccine strain compositions. Herein, we describe the development and applications of a quantitative risk calculator that predicts relative immune escape of SARS-CoV-2 variants using a statistical modeling framework. The approach integrates large-scale, experimentally derived spike-antibody epitope and escape maps with serum neutralization data generated using pseudotyped viruses and clinical sera. By aggregating site-level escape information into a strain-level metric, the calculator enables the grouping of antigenically related SARS-CoV-2 variants to guide strain selection for at-risk vaccine design and preparation, in anticipation of seasonal strain change recommendations by global public health agencies and the WHO. Here, we demonstrate the utility of this framework through retrospective and prospective strain selection exercises for the XBB.1.5-, JN.1/KP.2-, and LP.8.1-adapted mRNA-1273 COVID-19 vaccines during the 2023-2026 seasons, respectively. In all cases, model predictions were largely supported by clinical immunogenicity data and aligned with subsequent recommendations by global public health agencies.IMPORTANCEWe present a framework to estimate the relative immune escape potential of emerging variants by integrating previously published experimental epitope-level escape data with serum neutralization measurements. By consolidating mutation-level effects into a strain-level metric, this approach enables classification of antigenically similar variants. Retrospective and prospective applications demonstrate that model-based assessments are consistent with observed immunogenicity data. This framework provides a practical tool to support preparedness efforts by informing at-risk vaccine development activities in advance of seasonal strain selection guidance.

The mouse model of tick-mediated Borrelia burgdorferi sensu lato (Bbsl) challenge is integral to the preclinical evaluation of Lyme disease vaccines. The standard measure of vaccine efficacy is the recovery of viable spirochetes from different mouse tissues, monitored weekly for a month post challenge. Serological tests (ELISA and Western blots) with B. burgdorferi lysates, recombinant proteins, or peptides are often used as alternative or confirmatory readouts. While there are several reports suggesting that culture positivity and serology are strongly correlated, a systematic study addressing this issue is lacking. In this report, we took advantage of available data sets from large cohorts of naive and OspA actively and passively immunized mice that had been challenged with Ixodes scapularis nymphs carrying Bbsl strain B31, euthanized 3 weeks later, then assessed for culture positivity across different tissue types (ear, skin, ankle, bladder, and heart) and seropositivity using an OspC and DbpB 2-plex microsphere immunoassay (MIA) and a vmp-like sequence C6 monoplex MIA. Our results demonstrate a 96.5%-97% agreement between culture positivity and seroconversion using the OspC/DbpB and C6 MIAs, suggesting that serology provides a near-perfect readout of disseminated spirochetal infection. While some instances of culture and serological discordance could be attributed to technical errors, others likely reflect aspects of infectivity/immunological dynamics, including the possibility of abortive (non-sterilizing) B. burgdorferi infections. We conclude that serological testing provides a highly accurate and practical measure of disseminated B. burgdorferi infection in mouse models, crucial for the efficient preclinical assessment of Lyme disease vaccines. IMPORTANCE:The laboratory mouse (Mus musculus) plays an indispensable role in the testing of candidate vaccines for Lyme disease, an emerging tick-borne infection caused by the spirochete, Borrelia burgdorferi. While laboratory mice do not develop Lyme disease per se, B. burgdorferi proliferates in skin tissues following a tick bite, then disseminates to other organs over the course of days to weeks. In this report, we examined the concordance between two widely used methodologies to assess disseminated B. burgdorferi infection and offer recommendations to standardize testing across laboratories.

The continued diversification of SARS-CoV-2 omicron lineage has given rise to the JN.1 variant and descendant strains (KP.2, KP.3, and XEC) that have prolonged the JN.1 infection wave. JN.1 and KP.2 show decreased susceptibility to neutralization sera in recipients of XBB.1.5 vaccine boosters, supporting the recent authorization of JN.1- and KP.2-matched mRNA vaccines in the United States, Europe, and other regions. We evaluated the immunogenicity of two updated monovalent variant-containing formulations of mRNA-1273 vaccines encoding the spike protein of the omicron subvariants JN.1 (mRNA-1273.167) and KP.2 (mRNA-1273.712) as compared with the monovalent XBB.1.5 vaccine (mRNA-1273.815). The vaccines were administered either as a two-dose primary series in naive mice or as a booster (third) dose in mice previously immunized with two-dose primary series of mRNA-1273 (ancestral strain). The neutralizing antibody response elicited by these vaccines against JN.1 subvariants (KP.3 and LA.2) and the recombinant strain (XEC), which achieved dominance in the United States during late 2024, was evaluated. Primary series immunization with either JN.1- or KP.2-matched vaccine elicited robust neutralizing antibody titers against the matched strains and effectively cross-neutralized KP.3, LA.2, and XEC, but not the antigenically distant XBB.1.5. Similarly, JN.1- and KP.2-matched vaccines administered as a booster (third) dose increased titers against the corresponding strains and JN.1-related subvariants, but not against XBB.1.5. These data suggest these strains are antigenically similar with relatively few spike differences between JN.1 and KP.2/JN.1-related subvariants. Our results demonstrate the potency of JN.1- and KP.2-containing mRNA-1273 vaccines in neutralizing the matched variants and their utility in cross-neutralizing JN.1-related subvariants KP.3, LA.2, and XEC. Taken together, these data suggest that the licensed JN.1 and KP.2 mRNA vaccines are likely to continue to protect against the emerging strains as the JN.1 lineage further evolves.

Messenger RNA (mRNA) has emerged as a highly effective and versatile platform for vaccine delivery. We previously designed a virus-like particle (VLP)-forming env-gag mRNA vaccine against human immunodeficiency virus-1 (HIV-1) that elicited envelope-specific neutralizing antibodies and protection from heterologous simian-human immunodeficiency virus (SHIV) infection in rhesus macaques. Here, we introduce a key technological advance to this platform by inclusion of mRNA encoding a retroviral protease to process Gag and produce mature VLPs. Appropriately dosed and timed expression of the protease was achieved using a full-length gag-pol mRNA transcript. Addition of gag-pol mRNA to an HIV-1 env-gag mRNA vaccine resulted in enhanced titers of envelope trimer-binding and neutralizing antibodies in a mouse model. Analogous results were obtained with a hybrid Gag-based, VLP-forming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine expressing an engineered spike protein. Thus, inclusion of a retroviral protease can increase the immunogenicity of Gag-based, VLP-forming mRNA vaccines against human pathogens.

Chronic hepatitis B remains a major global health challenge, affecting over 254 million individuals and causing over 1 million deaths annually. Despite current antiviral therapies effectively suppressing viral replication, functional cure rates are low due to HBV-induced immune dysfunction and exhaustion. Therefore, new therapeutic approaches to achieve immune control of HBV infection are needed. Following the systematic evaluation of multiple HBV mRNA antigen designs, we developed mRNA-1965, a trivalent therapeutic mRNA vaccine encoding nanoparticle-displayed PreS1 and PreS2 domains of HBsAg to bypass the immune interference caused by HBV subviral particles, along with mutant forms of HBV Core and Polymerase. In HBV naïve mice, mRNA-1965 immunization induced dose-dependent HBV-neutralizing antibodies and Th1-skewed CD4+ and IFNγ+ CD8+ T cell responses to all three encoded HBV antigens. In non-human primates, mRNA-1965 elicited broad antibody and T cell responses across multiple HBV genotypes. Furthermore, vaccination with mRNA-1965 achieved a strong neutralizing antibody response and complete clearance of serum and liver HBV biomarkers in in an AAV-HBV mouse model with ∼100 IU/mL baseline HBsAg. Notably, combining mRNA-1965 with immune stimulatory co-modalities targeting PD-L1 and OX40 further enhanced therapeutic efficacy in mice with ∼1000 IU/mL baseline HBsAg. Clearance of HBV in AAV-HBV mice was associated with T cell response to mRNA-encoded antigens and with activation and differentiation of Core-specific CD8+ T cells. These findings support the potential of mRNA-1965 to promote a functional cure for chronic hepatitis B by overcoming immune dysfunction and subsequently enabling robust, functional immunity.

The first-ever recent Marburg virus (MARV) outbreak in Tanzania and recent emergences in Rwanda, Ghana and Equatorial Guinea underscore the importance of therapeutic or vaccine development against the virus, for which none are approved. mRNA vaccines were proven successful in a pandemic-response to severe acute respiratory syndrome coronavirus-2, making it an appealing platform to target pathogenic emerging viruses. Here, we develop 1-methyl-pseudouridine-modified mRNA vaccines formulated in lipid nanoparticles (LNP) targeting the glycoproteins (GP) of MARV and the closely-related Ravn virus (RAVV). Vaccination of female guinea pigs elicits robust binding and neutralizing antibodies and confers complete protection against homologous and heterologous virus replication, disease and death. Characterization of antibody responses identifies disparities in the binding and functional profiles between the two viruses and regions in GP that are broadly reactive. The glycan cap is highlighted as an immunoreactive site for orthomarburgviruses, inducing antibody responses that are virus dependent. Profiling the antibody responses against the two viruses provides insight into how antigenic differences may affect the response towards conserved GP regions, which would otherwise be predicted to be cross-reactive, and has implications for the future design of broadly protective vaccines. The results support the use of mRNA-LNPs against pathogens of high consequence.

Although virus-like particle (VLP) vaccines were shown to be effective against several viruses, their advantage over vaccines that include envelope protein only is not completely clear, particularly for mRNA-encoded VLPs. We conducted a side-by-side comparison of the immunogenicity and protective efficacy of mRNA vaccines encoding the Marburg virus (MARV) full-length glycoprotein (GP) delivered alone or as a VLP. Electron microscopy confirmed VLP formation when MARV GP and matrix protein VP40 were coexpressed. We vaccinated guinea pigs with a 2-component mRNA vaccine encoding GP and VP40 (VLP) or GP alone. At the highest dose, both vaccines protected fully, although the VLP vaccine elicited a slightly lower humoral response than did the GP-only mRNA vaccine. However, at low doses, GP-only mRNA conferred 100% protection, whereas the VLP vaccine conferred only partial protection. In mice, VLP mRNA induced a moderate preference for GP-specific CD8+ T cell responses, whereas the GP-only mRNA somewhat favored CD4+ T cell responses. Guinea pig whole-blood RNA-Seq revealed that the VLP vaccine downregulated genes associated with various biological and metabolic processes, including the NF-κB signaling pathway, whereas the GP-only vaccine upregulated IFN signaling. Overall, the VLP mRNA vaccine was less immunogenic and protective, whereas the GP-only mRNA vaccine conferred robust protection with a dose of as little as 1 μg in guinea pigs.

Germline-targeting is a promising approach to HIV vaccine development that begins with the elicitation of precursors to broadly neutralizing antibodies (bnAbs), but it remains unclear whether simultaneous elicitation of precursors to multiple epitopes on the HIV envelope (Env) would be inhibited by competition. This study used preclinical mouse models with physiologically relevant frequencies of bnAb precursor-bearing B cells to compare precursor elicitation by coadministration of multiple protein or mRNA lipid nanoparticle (mRNA-LNP) germline-targeting immunogens. These immunogens activate multiple bnAb precursor classes targeting distinct epitopes on Env but with evidence of potential competition. Simultaneous delivery of immunogens encoded by mRNA-LNPs, however, drove maturation across different precursor frequencies and immunogen doses. Furthermore, administration of a cocktail of mRNA-LNP immunogens (N332-GT5 gp151, ApexGT5 gp151, eOD-GT8 60mer, and 10E8-GT12 24mer) led to balanced activation of four distinct bnAb precursor classes, indicating that multiepitope HIV bnAb precursor priming might be successfully implemented in humans but might be immunogen dependent.

Breast milk provides a rich source of naturally derived maternal antibodies that confer passive immunity to infants, protecting them from a variety of respiratory and enteric infections. For at-risk newborns in low- and middle-income countries, supplementing breast milk with pathogen-specific neutralizing and bactericidal antibodies could offer significant short- and long-term health benefits. In this study, we explored the use of mRNA and lipid nanoparticle (LNP) technology to deliver a Vibrio cholerae-specific monoclonal IgG antibody (ZAC-3) into the milk of lactating mice. Swiss Webster mice were intravenously administered ZAC-3 IgG mRNA-LNPs, and we monitored serum and breast milk for the presence of V. cholerae-specific human IgG1. A single injection of mRNA-LNPs led to rapid and sustained expression of ZAC-3 IgG in both the blood and breast milk of lactating dams. ZAC-3 IgG1 in these samples recognized whole V. cholerae cells by ELISA and exhibited potent vibriocidal activity in the presence of human complement. Furthermore, ZAC-3 IgG was detected in the sera of suckling pups at levels proportional to those in the mothers, demonstrating successful transfer of functional antibodies to the newborns. In conclusion, our findings highlight the potential of mRNA-based monoclonal antibody platforms in the maternal-newborn context and address key challenges associated with the direct delivery of recombinant antibodies. ### Competing Interest Statement CED, AC, OJP are or were employees of and shareholders in Moderna Inc. CED and OJP are co-inventors on international patent WO 2022/212191 A1.

The ongoing adaptive evolution of SARS-CoV-2 is characterized by the continued emergence of novel variants that escape from previously acquired infection- and/or vaccination-derived immunity. This continued SARS-CoV-2 variant evolution has necessitated annual vaccine updates to better match circulating viral variants. To optimize protection against emerging variants of interest and concern, a reliable means of predicting the immune escape of novel variants is needed to enable at-risk preparation of new vaccines. Herein, we describe the development and applications of a risk calculator that uses statistical modeling to predict the immune escape of emerging variants. The calculator utilizes previously published spike-antibody epitope and escape profiles and in vitro neutralization assessment of a large panel of pseudotyped SARS-CoV-2 variants evaluated against clinical sera. The calculator enables the grouping of antigenically related SARS-CoV-2 variants to guide strain selection for at-risk vaccine design and preparation, in anticipation of potential future requests by the global public health agencies. Here, we demonstrated the strain selection exercises for the XBB.1.5- and JN.1/KP.2-adapted mRNA-1273 COVID-19 vaccines in the 2023-2024 and 2024-2025 seasons, respectively, which were supported by both the risk calculator and preclinical and clinical immunogenicity data and were later recommended by the global public health agencies. ### Competing Interest Statement All authors are employees of Moderna, Inc., and hold stock/stock options in the company. Moderna, Inc., N/A

The continued evolution of the SARS-CoV-2 Omicron JN.1 lineage has led to the emergence of antigenically distinct subvariants including KP.2, KP.3, XEC, and LP.8.1, which became the dominant strains in the Americas and Europe by mid-2025. LP.8.1 was designated a Variant Under Monitoring by the WHO in January 2025 due to its potential to displace prior circulating variants. Informed by early growth modeling and antigenic analysis, we selected LP.8.1 as a candidate strain for the 2025-2026 vaccine season. Here, we describe the development of updated LP.8.1-matched mRNA vaccine compositions encoding either the full-length spike protein for mRNA-1273 (monovalent) or the membrane-anchored receptor-binding and N-terminal domains for the mRNA-1283 vaccine. Initial in vitro characterization, including structural analysis, demonstrated robust antigen expression and intact antigenic features. Immunogenicity of both vaccines were evaluated in murine models following immunization as either a primary series in naïve animals or as a booster dose. LP.8.1-matched vaccines elicited strong neutralizing antibody responses against the homologous LP.8.1 strain and more recently emerging JN.1-lineage subvariants, including XFG and NB.1.8.1. Notably, the mRNA-1283 vaccine expressing LP.8.1 induced higher mean neutralization titers than the mRNA-1273 version across multiple variants. These data demonstrate the immunogenicity and breadth of both LP.8.1-based mRNA-1273 and mRNA-1283 vaccines in the context of ongoing JN.1 lineage evolution and support the selection of LP.8.1 as the updated vaccine antigen for the 2025-2026 season. ### Competing Interest Statement All authors are employees of Moderna and may own stock and/or stock options in the company. The authors declare no other competing interests.

Respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract disease in young children and older adults. We designed a codon-optimized mRNA vaccine, mRNA-1345, encoding the RSV F-glycoprotein stabilized in the prefusion (preF) conformation and with a deletion at the cytoplasmic tail. mRNA-1345 cell surface protein expression was higher and detected for longer versus previous mRNA-based RSV vaccine candidates evaluated clinically. In rodent models, mRNA-1345 induced a robust neutralizing and preF-biased antibody response, a T helper 1-biased cellular response, and demonstrated dose-dependent protection against RSV challenge with no evidence of enhanced respiratory disease. These results supported initial clinical evaluation of mRNA-1345 in adults, children, and RSV-naïve infants; mRNA-1345 was recently demonstrated to be efficacious against RSV disease in older adults in a pivotal efficacy study.

In 2022, mpox virus (MPXV) spread worldwide, causing 99,581 mpox cases in 121 countries. Modified vaccinia Ankara (MVA) vaccine use reduced disease in at-risk populations but failed to deliver complete protection. Lag in manufacturing and distribution of MVA resulted in additional MPXV spread, with 12,000 reported cases in 2023 and an additional outbreak in Central Africa of clade I virus. These outbreaks highlight the threat of zoonotic spillover by Orthopoxviruses. mRNA-1769, an mRNA-lipid nanoparticle (LNP) vaccine expressing MPXV surface proteins, was tested in a lethal MPXV primate model. Similar to MVA, mRNA-1769 conferred protection against challenge and further mitigated symptoms and disease duration. Antibody profiling revealed a collaborative role between neutralizing and Fc-functional extracellular virion (EV)-specific antibodies in viral restriction and ospinophagocytic and cytotoxic antibody functions in protection against lesions. mRNA-1769 enhanced viral control and disease attenuation compared with MVA, highlighting the potential for mRNA vaccines to mitigate future pandemic threats.

The messenger RNA (mRNA) platform emerged at the forefront of vaccine development during the COVID-19 pandemic, with two mRNA COVID-19 vaccines being among the first authorized globally. These vaccines were developed rapidly. Informed by decades of laboratory research, and proved to be safe and efficacious tools for mitigating the global impact of the COVID-19 pandemic. The mRNA platform holds promise for a broader medical application beyond COVID-19. Herein, we provide an overview of this platform and describe lessons learned from the COVID-19 pandemic to help formulate strategies toward enhancing uptake of future mRNA-based interventions. We identify several strategies as vital for acceptance of an expanding array of mRNA-based vaccines and therapeutics, including education, accurate and transparent information sharing, targeted engagement campaigns, continued investment in vaccine safety surveillance, inclusion of diverse participant pools in clinical trials, and addressing deep-rooted inequalities in access to healthcare. We present findings from the Global Listening Project (GLP) initiative, which draws on quantitative and qualitative approaches to capture perceptions and experiences during the COVID-19 pandemic to help design concrete action plans for improving societal preparedness for future emergencies. The GLP survey (>70,000 respondents in 70 countries) revealed tremendous disparities across countries and sociodemographic groups regarding willingness to accept novel mRNA vaccines and medicines. The comfort in innovations in mRNA medicines was generally low (35%) and was marginally lower among women (33%). The GLP survey and lessons learnt from the COVID-19 pandemic provide actionable insights into designing effective strategies to enhance uptake of future mRNA-based medicines.

ABSTRACT Background The MF59-adjuvanted gB subunit (gB/MF59) vaccine demonstrated ~50% efficacy against human cytomegalovirus (HCMV) acquisition in multiple clinical trials, suggesting efforts to improve this vaccine design might yield a vaccine suitable for licensure. A vaccine candidate employing nucleoside-modified mRNAs encoding HCMV gB and pentameric complex (PC) encapsulated in lipid nanoparticle, mRNA-1647, is currently in late-stage efficacy trials. Yet, its immunogenicity has not been compared to the partially-effective gB/MF59 vaccine. Methods We assessed neutralizing and Fc-mediated IgG effector antibody responses induced by mRNA-1647, a vaccine comprising an equal mass of 6 mRNAs encoding gB and PC antigens, in both HCMV seropositive and seronegative vaccinees from a first-in-human clinical trial through 1-year following 3 rd vaccination using a systems serology approach. Further, we compared peak anti-gB antibody responses in seronegative mRNA-1647 vaccinees to that of seronegative female adolescent gB/MF59 vaccine recipients. Results mRNA-1647 vaccination boosted pre-existing HCMV-specific IgG responses in seropositive vaccinees, including neutralizing and Fc-mediated effector antibody responses. In seronegative vaccinees, mRNA-1647 induced durable and functional HCMV-specific IgG responses. Elicited gB-specific IgG responses were lower than the PC-specific IgG responses. Additionally, gB-specific IgG and antibody-dependent cellular phagocytosis (ADCP) responses were lower than those elicited by gB/MF59. However, mRNA-1647 elicited robust neutralization and high antibody-dependent cellular cytotoxicity (ADCC) responses. Conclusions mRNA-1647 vaccination induced polyfunctional and durable HCMV-specific antibody responses. mRNA-1647-elicited gB-specific IgG responses were lower than PC-specific IgG responses and lower than those elicited by the partially effective gB/MF59. However, higher neutralization and ADCC responses were elicited by mRNA-1647 than gB/MF59. Clinical Trials Registration ClinicalTrials.gov ( NCT03382405 , mRNA-1647) and ( NCT00133497 , gB/MF59). Summary mRNA-1647 HCMV vaccine elicited polyfunctional and durable antibody responses in humans. While the mRNA-1647-elicited glycoprotein B (gB)-specific IgG responses were lower than that of the moderately-effective gB/MF59 vaccine, the pentameric complex (PC)-specific IgG responses were strong.