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Messenger RNA (mRNA) vaccines are being used to combat the spread of COVID-19 (refs. 1 – 3 ), but they still exhibit critical limitations caused by mRNA instability and degradation, which are major obstacles for the storage, distribution and efficacy of the vaccine products 4 . Increasing secondary structure lengthens mRNA half-life, which, together with optimal codons, improves protein expression 5 . Therefore, a principled mRNA design algorithm must optimize both structural stability and codon usage. However, owing to synonymous codons, the mRNA design space is prohibitively large—for example, there are around 2.4 × 10 632 candidate mRNA sequences for the SARS-CoV-2 spike protein. This poses insurmountable computational challenges. Here we provide a simple and unexpected solution using the classical concept of lattice parsing in computational linguistics, where finding the optimal mRNA sequence is analogous to identifying the most likely sentence among similar-sounding alternatives 6 . Our algorithm LinearDesign finds an optimal mRNA design for the spike protein in just 11 minutes, and can concurrently optimize stability and codon usage. LinearDesign substantially improves mRNA half-life and protein expression, and profoundly increases antibody titre by up to 128 times in mice compared to the codon-optimization benchmark on mRNA vaccines for COVID-19 and varicella-zoster virus. This result reveals the great potential of principled mRNA design and enables the exploration of previously unreachable but highly stable and efficient designs. Our work is a timely tool for vaccines and other mRNA-based medicines encoding therapeutic proteins such as monoclonal antibodies and anti-cancer drugs 7 , 8 . An algorithm based on concepts established in computational linguistics enables rapid principled design of mRNA vaccines optimizing both structural stability and codon usage, resulting in improved half-life, protein expression and immune responses.

The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans 1 . CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12 μg lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham ( n  = 6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates. CV2CoV, a second-generation mRNA COVID-19 vaccine with non-modified nucleosides but optimized non-coding regions, is demonstrated to be effective against SARS-CoV-2 challenge when tested in non-human primates.

Immune imprinting is a phenomenon in which prior antigenic experiences influence responses to subsequent infection or vaccination 1 , 2 . The effects of immune imprinting on serum antibody responses after boosting with variant-matched SARS-CoV-2 vaccines remain uncertain. Here we characterized the serum antibody responses after mRNA vaccine boosting of mice and human clinical trial participants. In mice, a single dose of a preclinical version of mRNA-1273 vaccine encoding Wuhan-1 spike protein minimally imprinted serum responses elicited by Omicron boosters, enabling generation of type-specific antibodies. However, imprinting was observed in mice receiving an Omicron booster after two priming doses of mRNA-1273, an effect that was mitigated by a second booster dose of Omicron vaccine. In both SARS-CoV-2-infected and uninfected humans who received two Omicron-matched boosters after two or more doses of the prototype mRNA-1273 vaccine, spike-binding and neutralizing serum antibodies cross-reacted with Omicron variants as well as more distantly related sarbecoviruses. Because serum neutralizing responses against Omicron strains and other sarbecoviruses were abrogated after pre-clearing with Wuhan-1 spike protein, antibodies induced by XBB.1.5 boosting in humans focus on conserved epitopes targeted by the antecedent mRNA-1273 primary series. Thus, the antibody response to Omicron-based boosters in humans is imprinted by immunizations with historical mRNA-1273 vaccines, but this outcome may be beneficial as it drives expansion of cross-neutralizing antibodies that inhibit infection of emerging SARS-CoV-2 variants and distantly related sarbecoviruses. In mouse experiments and in clinical trials in humans, boosting with Omicron-specific mRNA following immunization with Wuhan-1 spike mRNA results in immune responses focused on conserved rather than variant-specific epitopes.

In the prevention and treatment of infectious diseases, mRNA vaccines hold great promise because of their low risk of insertional mutagenesis, high potency, accelerated development cycles, and potential for low-cost manufacture. In past years, several mRNA vaccines have entered clinical trials and have shown promise for offering solutions to combat emerging and re-emerging infectious diseases such as rabies, Zika, and influenza. Recently, the successful application of mRNA vaccines against COVID-19 has further validated the platform and opened the floodgates to mRNA vaccine’s potential in infectious disease prevention, especially in the veterinary field. In this review, we describe our current understanding of the mRNA vaccines and the technologies used for mRNA vaccine development. We also provide an overview of mRNA vaccines developed for animal infectious diseases and discuss directions and challenges for the future applications of this promising vaccine platform in the veterinary field.

Pregnancy is a known risk factor for severe Coronavirus disease 2019. It is important to develop safe vaccines that elicit strong maternal and fetal antibody responses. Registries (ClinicalTrials.gov, the WHO Clinical Trial Registry, and the European Union Clinical Trial Registry) and databases (MEDLINE, ScienceDirect, Cochrane Library, Proquest, Springer, medRxiv, and bioRxiv) were systematically searched in June 20-22, 2021, for research articles pertaining to Covid-19 and pregnancy. Manual searches of bioRxiv and medRxiv were also conducted. Inclusion criteria were studies that focused on Covid-19 vaccination among pregnant women, while review articles and non-human studies were excluded. Infection rate, maternal antibody response, transplacental antibody transfer, and adverse events were described. There were 13 observational studies with a total of 48,039 pregnant women who received mRNA vaccines. Of those, three studies investigated infection rate, six studies investigated maternal antibody response, seven studies investigated antibody transfer, three studies reported local adverse events, and five studies reported systemic adverse events. The available data suggested that the mRNA-based vaccines (Pfizer-BioNTech and Moderna) can prevent future SARS-CoV-2 infection. These vaccines did not show clear harm in pregnancy. The most commonly encountered adverse reactions were pain at the injection site, fatigue, and headache, but these were transient. Antibody responses were rapid after the first vaccine dose. After the booster, antibody responses were stronger and associated with better transplacental antibody transfer. Longer intervals between first vaccination dose and delivery were also associated with higher antibody fetal IgG and a better antibody transfer ratio. The SARS-CoV-2 mRNA vaccines are encouraged for pregnancy. These vaccines can be a safe option for pregnant women and their fetuses. Two vaccine doses are recommended for more robust maternal and fetal antibody responses. Longer latency is associated with higher fetal antibody responses. Further research about its long-term effect on pregnancy is needed. PROSPERO (CRD42021261684).

Messenger RNA (mRNA) vaccines offer an adaptable and scalable platform for cancer immunotherapy, requiring optimal design to elicit a robust and targeted immune response. Recent advancements in bioinformatics and artificial intelligence (AI) have significantly enhanced the design, prediction, and optimization of mRNA vaccines. This paper reviews technologies that streamline mRNA vaccine development, from genomic sequencing to lipid nanoparticle (LNP) formulation. We discuss how accurate predictions of neoantigen structures guide the design of mRNA sequences that effectively target immune and cancer cells. Furthermore, we examine AI-driven approaches that optimize mRNA-LNP formulations, enhancing delivery and stability. These technological innovations not only improve vaccine design but also enhance pharmacokinetics and pharmacodynamics, offering promising avenues for personalized cancer immunotherapy.

Researchers look ahead to the potential uses and benefits of a technology that has been more than 20 years in the making. Researchers look ahead to the potential uses and benefits of a technology that has been more than 20 years in the making. Credit: Pascal Pochard-Casabianca/AFP via Getty A man receives a dose of Comirnaty Omicron XBB 1.5 Pfizer vaccine for COVID-19 at a pharmacy in Corsica, France.

mRNA cancer vaccines demonstrate potential in clinical trials, but existing platforms struggle to boost antitumor efficacy without added cost or complexity. Here, we present a streamlined linear cap-independent mRNA (LciRNA) cancer vaccine platform, achieved by fusing a UPA protective sequence, composed of a viral exoribonuclease-resistant RNA (xrRNA) and a poly(A) binding protein (PABP) motif, to an optimized Enterovirus A internal ribosome entry site. UPA impedes exonuclease-mediated decay and recruits RNA-binding proteins to stabilize LciRNA, enabling stable in vivo expression without 5’ capping or modifications. Moreover, LciRNA innately stimulates immune responses by engaging pattern-recognition receptors, promoting dendritic cell maturation, and upregulating proinflammatory signals. In murine melanoma and HPV-associated tumor models, this vaccine platform elicits strong systemic and intra-tumoral T cell responses, achieving superior tumor control, demonstrating how immune stimulation-translation synergy underpins its efficacy. Thus, we present a cost-effective platform with enhanced efficacy, and highlight coupled immune stimulation and translation as a paradigm for future mRNA cancer vaccines. mRNA vaccines hold promise as cancer therapeutics. However, production complexity and prohibitive manufacturing costs limit the applicability of these vaccine platforms. Here, the authors present an engineered linear Cap-independent mRNA vaccine design that achieves stable in vivo expression and elicits robust anti-tumor immune responses in preclinical mouse models.

Bacterial infections have accompanied humanity for centuries. The discovery of the first antibiotics and the subsequent golden era of their discovery temporarily shifted the balance in this confrontation to the side of humans. Nevertheless, the excessive and improper use of antibacterial drugs and the evolution of bacteria has gotten the better of humans again. Therefore, today, the search for new antibacterial drugs or the development of alternative approaches to the prevention and treatment of bacterial infections is relevant and topical again. Vaccination is one of the most effective strategies for the prevention of bacterial infections. The success of new-generation vaccines, such as mRNA vaccines, in the fight against viral infections has prompted many researchers to design mRNA vaccines against bacterial infections. Nevertheless, the biology of bacteria and their interactions with the host’s immunity are much more complex compared to viruses. In this review, we discuss structural features and key mechanisms of evasion of an immune response for nine species of bacterial pathogens against which mRNA vaccines have been developed and tested in animals. We focus on the results of experiments involving the application of mRNA vaccines against various bacterial pathogens in animal models and discuss possible options for improving the vaccines’ effectiveness. This is one of the first comprehensive reviews of the use of mRNA vaccines against bacterial infections in vivo to improve our knowledge.

The monkeypox virus ( MPXV ) is a newly discovered zoonotic orthopoxvirus that can infect humans and shares similarities with the smallpox virus . With no clinically validated treatment for MPXV infections, it is important to develop a broad-range vaccine that is effective against this disease. This study aimed to design novel multiple-epitope DNA and mRNA vaccines against MXPV using comprehensive immunoinformatics and reverse vaccinology techniques. Eleven MPXV proteins were selected from the UniProt database and assessed for their antigenicity and allergenicity. Proteins exhibiting significant antigenicity and non-allergenic characteristics were examined for the prediction of T-cell and B-cell epitopes. Four MHC-I, eight MHC-II, and six B-cell epitopes were coupled with specific linkers and adjuvant peptide sequences to boost the immunological response to the developed vaccine. The designed vaccines showed antigenic nature with a 0.5936 score and solubility nature with a 0.513 score, and its GRAVY score of 0.147 indicates their hydrophilic nature. Structural validation confirmed the superior tertiary structure of the designed vaccines. Molecular docking studies demonstrated a robust interaction between human TLR-8 and the developed vaccines, with a docking score of -1208.2 kcal/mol, and Moleculae Dynamics (MD) simulations confirmed its stability. The immune simulation results indicated that vaccination strongly stimulated immunity, resulting in high concentrations of IgG and IgM antibodies. Cloning analysis and in silico restriction prediction demonstrated the viability of integrating the developed vaccine into an Escherichia coli ( E. coli) expression system. Furthermore, an mRNA vaccine was developed by incorporating a 5′ cap, 5′ untranslated region (UTR), Kozak sequence, and tissue plasminogen activator (tPA) with the CD40 ligand (CD40L) linked to the selected epitopes using EAAAK linkers. A poly (A) tail, MITD1, and 3′ UTR were appended to the 3′ end of the construct. The mRNA vaccine design incorporated codon optimization, resulting in a CAI score 0.83 and GC content of 60.46%, indicating efficient vaccine expression within host cells. Analysis of several parameters revealed that the architecture of the synthesized mRNA was stable with MFE: -2170.70 kcal/mol. These outcomes may contribute to the development of an experimental MPXV vaccine with stronger potency and superior safety measures. Additional in vitro and in vivo experiments are required to test the safety and efficacy of these newly developed vaccines. Highlights MPXV proteins were selected and assessed for safety and efficacy as potential vaccine targets. Four MHC-I, eight MHC-II, and six B-cell epitopes were identified and combined with an adjuvant to design the final vaccine. The vaccine demonstrated favorable interactions with human TLR-8 and exhibited good stability. The experimental results demonstrated a significant enhancement in the immune response, characterized by increased levels of IgG and IgM. An mRNA vaccine was developed with specific sequences to improve cellular efficacy, with a GC content of 60.46%. Both protein-based and mRNA vaccines have shown promising results in laboratory tests.