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Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer–BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax). Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8–12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311. Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation. Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification. UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.

mRNA vaccines have been demonstrated as a powerful alternative to traditional conventional vaccines because of their high potency, safety and efficacy, capacity for rapid clinical development, and potential for rapid, low-cost manufacturing. These vaccines have progressed from being a mere curiosity to emerging as COVID-19 pandemic vaccine front-runners. The advancements in the field of nanotechnology for developing delivery vehicles for mRNA vaccines are highly significant. In this review we have summarized each and every aspect of the mRNA vaccine. The article describes the mRNA structure, its pharmacological function of immunity induction, lipid nanoparticles (LNPs), and the upstream, downstream, and formulation process of mRNA vaccine manufacturing. Additionally, mRNA vaccines in clinical trials are also described. A deep dive into the future perspectives of mRNA vaccines, such as its freeze-drying, delivery systems, and LNPs targeting antigen-presenting cells and dendritic cells, are also summarized.

In a placebo-controlled, phase 2–3 trial, one dose of mRNA-1345 led to a lower incidence of RSV disease among adults 60 years of age or older. Solicited local and systemic adverse reactions occurred more often with the vaccine.

The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8⁺ T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen–bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2180–188)–encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti–programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.

mRNA vaccines have tremendous potential to fight against cancer and viral diseases due to superiorities in safety, efficacy and industrial production. In recent decades, we have witnessed the development of different kinds of mRNAs by sequence optimization to overcome the disadvantage of excessive mRNA immunogenicity, instability and inefficiency. Based on the immunological study, mRNA vaccines are coupled with immunologic adjuvant and various delivery strategies. Except for sequence optimization, the assistance of mRNA-delivering strategies is another method to stabilize mRNAs and improve their efficacy. The understanding of increasing the antigen reactiveness gains insight into mRNA-induced innate immunity and adaptive immunity without antibody-dependent enhancement activity. Therefore, to address the problem, scientists further exploited carrier-based mRNA vaccines (lipid-based delivery, polymer-based delivery, peptide-based delivery, virus-like replicon particle and cationic nanoemulsion), naked mRNA vaccines and dendritic cells-based mRNA vaccines. The article will discuss the molecular biology of mRNA vaccines and underlying anti-virus and anti-tumor mechanisms, with an introduction of their immunological phenomena, delivery strategies, their importance on Corona Virus Disease 2019 (COVID-19) and related clinical trials against cancer and viral diseases. Finally, we will discuss the challenge of mRNA vaccines against bacterial and parasitic diseases.

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.

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.

mRNA-based vaccines can be rapidly manufactured and have been demonstrated clinically to raise robust immune responses to COVID-19 and protect against severe COVID-19 disease. The clinical immunogenicity and efficacy of self-amplifying mRNA (sa-mRNA) vaccines have also been demonstrated, along with a longer duration of action than mRNA vaccines. However, a detailed understanding of differences between sa-mRNA and conventional mRNA vaccines with modified bases is lacking. Compared with a N1ψ-modified mRNA platform, when using an sa-mRNA approach, we observed a > 100-fold greater transfection efficiency for multiple antigens by sa-mRNA, all of which also showed high durability for gene-of-interest (GOI) production. The enhanced magnitude and durability of GOI expression by sa-mRNA compared with modified mRNA was also analysed in vivo using a luciferase reporter construct. In this experiment, sa-mRNA produced >100-fold cumulative bioluminescence compared with an mRNA construct. The elevation in GOI production translated into greater in vivo immunogenicity, where a 10-fold lower dose of sa-mRNA generated similar binding and neutralizing titers for the avian pandemic influenza H5N1 strain in both mouse and rat models. The sa-mRNA construct also generated comparable or higher antigen-specific CD8 T cell responses at 10-fold lower doses than mRNA. The lower doses of sa-mRNA generated a reduced elevation of reactogenic biomarkers while still generating similar or higher immunogenicity in rats and mice compared with modified mRNA. The current study suggests the potential of leveraging dose sparing, improved durability, enhanced immunogenicity, and possibly reduced reactogenicity of the sa-mRNA platform for vaccine applications. •GOI expression with sa-mRNA vaccine is more potent and durable vs. mRNA vaccine.•Antibody titers and CD8 T cell responses are greater with sa-mRNA vs. mRNA vaccines.•sa-mRNA vaccine generates similar immunogenicity as mRNA vaccine at smaller doses.•Dose-spared sa-mRNA vaccine induces lower cytokine release than mRNA vaccine.

Both SARS-CoV-2 mRNA and mucosal vaccines induce protective immunity against COVID-19 but showed different immune profiles. We conducted a longitudinal head-to-head analysis of the safety and immunogenicity of the aerosolized adenovirus-vectored and mRNA COVID-19 vaccines. 450 participants were enrolled and randomly assigned into three groups to be vaccinated with an aerosolized Ad5-vectored bivalent vaccine (wild-type and BA.5, Ad5-CoV5T), an intramuscular bivalent mRNA vaccine (mbO5), and an aerosolized wild-type Ad5-vectored vaccine (Ad5-nCoV). The primary outcomes were adverse reactions within 28 days and anti-XBB.1.5-specific neutralizing antibody titers at day 28 after vaccination. The secondary outcome assessed safety within 30 min, serious adverse event within 6 months, and the persistence of anti-XBB.1.5/BA.5-specific neutralizing antibodies during the 6 months. Both the vaccines were well tolerated, but participants vaccinated with mbO5 reported more adverse reactions (73.3% mbO5 vaccinees vs. 28.7% aerosol vaccinees). No serious adverse events were recorded. The Ad5-CoV5T vaccine induced a superior anti-XBB.1.5-specific neutralizing titer than Ad5-nCoV at day 28 (geometric mean titer ratio of 1.48, 95% CI 1.12–1.97), while the mbO5 vaccine induced the highest antibody titer. The neutralizing antibodies were declined at month 6 and were similar across the three groups. In the pre-specified exploratory analysis, the mbO5 and the aerosolized vaccines induced comparable antigen-specific memory B cells but the latter stimulated higher frequency of IgA isotype and higher expression of CXCR3. This trial met the main hypothesis; the findings may provide insights for the development of the next-generation COVID-19 vaccines. Clinical Trials.gov identifier: NCT05886790. This trial evaluated the immunogenicity and safety profiles of a bivalent aerosolized adenovirus-vectored COVID-19 vaccine and an intramuscular bivalent mRNA booster. The mRNA booster induced higher neutralizing antibody levels and a distinct memory B cell response, yet was associated with a higher incidence of adverse reactions.