mRNA Vaccines Research Articles

Novel Less Toxic, Lymphoid Tissue-Targeted Lipid Nanoparticles Containing a Vitamin B5-Derived Ionizable Lipid for mRNA Vaccine Delivery.

Following their approval by the Food and Drug Administration, lipid nanoparticles (LNPs) have emerged as promising tools for delivering mRNA vaccines and therapeutics. Ionizable lipids are among the essential components of LNPs, as they play crucial roles in encapsulating mRNA and facilitating its release into the cytosol. In this study, 17 innovative ionizable lipids using vitamin B5 are designed as the core structure, aiming to reduce toxicity, to maintain vaccine efficiency, and to ensure synthetic feasibility. The top-performing LNP in terms of mRNA vaccine delivery in the mouse model is LNP 5097, which is generated by incorporating ionizable lipid I97. mRNA⊂LNP 5097 demonstrates favorable structural and physicochemical properties, high mRNA transfection efficiency, and long-term stability. Moreover, mRNA⊂LNP 5097 specifically delivers the mRNA to the spleen and lymph nodes in model mice, induces balanced Th1/Th2 immune responses, and elicits the production of high levels of neutralizing antibodies with low toxicity. The findings here suggest the high utility of LNP 5097, which includes novel vitamin B5-derived ionizable lipids with reduced toxicity, in mRNA vaccine research for both infectious diseases and cancer.

Comparative study of neutralizing antibodies titers in response to different types of COVID-19 vaccines among a group of egyptian healthcare workers.

Defining the protective thresholds against the severe-acute-respiratory-syndrome-relatedcorona virus-2 pandemic is a crucial challenge. To reduce the risks of severe disease, hospitalization, and death, various COVID-19 vaccines have been rapidly developed. This study aimed to assess the impact of three common COVID-19 vaccine types; two mRNA COVID-19 vaccines: (Pfizer/BioNTech's BNT162b2 and Moderna's mRNA-1273), one adenoviral vector vaccine: Oxford/AstraZeneca's ChAdOx1, and one inactivated vaccine (Sinovac Biotech/China's Sinovac) on the level of neutralizing antibodies, considering factors such as vaccine type, demographic characteristics, and hybrid immunity. We conducted a direct comparative analysis involving 300 healthcare workers, both with and without prior SARS-CoV-2 infection (B.1, C.36.3, and AY.32 (Delta) variants). Neutralizing antibodies levels were measured at baseline (before vaccination), before the second dose, and six months after the second dose. The results showed a significant increase in neutralizing antibodies levels after complete vaccination with all vaccine types. Among healthcare workers, those vaccinated with mRNA vaccines (Moderna or Pfizer) exhibited the highest neutralizing antibodies titers, followed by AstraZeneca, and finally Sinovac with the lowest titer. On studying the effect of previous COVID-19 infection after vaccination, no significant difference in neutralizing antibodies levels was observed between healthcare workers vaccinated with mRNA or AstraZeneca vaccines, both with prior COVID-19 infection, following the first and six months after the second dose. These findings suggest that individuals with prior COVID-19 may only require a single dose of mRNA or AstraZeneca vaccines to achieve a similar level of immunization as those without prior COVID-19 who completed the vaccination program. There is a significant increase in neutralizing antibodies levels after complete vaccination against COVID-19 Vaccination with mRNA vaccines exhibits the highest neutralizing antibodies titers. Vaccination with Sinovac exhibits the lowest neutralizing antibodies titers.

Advances in mRNA LNP-Based Cancer Vaccines: Mechanisms, Formulation Aspects, Challenges, and Future Directions

After the COVID-19 pandemic, mRNA-based vaccines have emerged as a revolutionary technology in immunization and vaccination. These vaccines have shown remarkable efficacy against the virus and opened up avenues for their possible application in other diseases. This has renewed interest and investment in mRNA vaccine research and development, attracting the scientific community to explore all its other applications beyond infectious diseases. Recently, researchers have focused on the possibility of adapting this vaccination approach to cancer immunotherapy. While there is a huge potential, challenges still remain in the design and optimization of the synthetic mRNA molecules and the lipid nanoparticle delivery system required to ensure the adequate elicitation of the immune response and the successful eradication of tumors. This review points out the basic mechanisms of mRNA-LNP vaccines in cancer immunotherapy and recent approaches in mRNA vaccine design. This review displays the current mRNA modifications and lipid nanoparticle components and how these factors affect vaccine efficacy. Furthermore, this review discusses the future directions and clinical applications of mRNA-LNP vaccines in cancer treatment.

Lipid nanoparticles as adjuvant of norovirus VLP vaccine augment cellular and humoral immune responses in a TLR9- and type I IFN-dependent pathway.

Norovirus (NoV) virus-like particles (VLPs) adjuvanted with aluminum hydroxide (Alum) are common vaccine candidates in clinical studies. Alum adjuvants usually inefficiently assist recombinant proteins to induce cellular immune responses. Thus, novel adjuvants are required to develop NoV vaccines that could induce both efficient humoral and robust cellular immune responses. Lipid nanoparticles (LNPs) are well-known mRNA delivery vehicles. Increasing evidence suggests that LNPs may have intrinsic adjuvant activity and can be used as adjuvants for recombinant protein vaccines; however, the underlying mechanism remains poorly understood. In this study, we compared the adjuvant effect of LNPs and Alum for a bivalent GI.1/GII.4 NoV VLP vaccine. Compared with Alum, LNP-adjuvanted vaccines induced earlier production of binding, blocking, and neutralizing antibodies and promoted a more balanced IgG2a/IgG1 ratio. It is crucial that LNP-adjuvanted vaccines induced stronger Th1-type cytokine-producing CD4+ T cell and CD8+ T cell responses than Alum. The adjuvant activity of LNPs depended on the ionizable lipid components. Mechanistically, LNPs activated innate immune responses in a type I IFN-dependent manner and were partially dependent on Toll-like receptor (TLR) 9, thus affecting the adaptive immune responses of the vaccine. This conclusion was supported by RNA-seq analysis and in vitro cell experiments and by the deeply blunted T cell responses in IFNαR1-/- mice immunized with LNP-adjuvanted vaccines. This study not only identified LNPs as a high quality adjuvant for NoV VLP vaccines, but also clarified the underlying mechanism of LNPs as a potent immunostimulatory component for improving protein subunit vaccines.IMPORTANCEWith the rapid development of mRNA vaccines, recurrent studies show that lipid nanoparticles (LNPs) have adjuvant activity. However, the mechanism of its adjuvant effect in protein vaccines remains unknown. In this study, we found that the LNP-adjuvanted norovirus bivalent virus-like particle vaccines led to durable antibody responses as well as Th1-type cytokine-producing CD4+ T cell and CD8+ T cell responses, which exceeded the efficiency of the conventional adjuvant aluminum hydroxide. Mechanistically, LNPs activated innate immune responses in a type I IFN-dependent manner and were partially dependent on Toll-like receptor 9, thus affecting the adaptive immune responses of the vaccine. This work unveils that LNPs as a potent immunostimulatory component may be ideal for generating CD8+ T cell and B cell responses for recombinant protein vaccines.

Virulence‐Free Reconstituted Synthetic Nanopathogen Empowered by Timely‐Activating TLR Agonist Promotes Heterologous Cancer Immunotherapy with Depletion of Tumor‐Specific Treg Cells

AbstractThe heterologous immunity of live pathogens leads to the emergence of this approach as a pivotal component in cancer immunotherapy. However, virulence, inflammatory‐related toxicity, and the induction of Treg cells after treatment hinder their clinical translation. Here, to exploit the heterologous immunity of live pathogens without risks, a virulence‐free reconstituted synthetic nanopathogen (RSnP) is developed by the cell wall skeleton of disrupted Mycobacterium bovis and the incorporation of timely‐activating Toll‐like receptor 7/8 agonists of which multifaceted activities can be promoted by endolysosomal enzymes. Immunization with RSnP, even without tumor‐specific antigens, exhibits potent antitumor efficacy against melanoma, breast cancer, and bladder cancer by promoting antitumor effector cells (CD8+ T cells, NK cells, M1 macrophages, and Th17 cells) and proinflammatory cytokines (IL‐12p70, TNF‐α, and IL‐6) while simultaneously mitigating immunosuppressive myeloid cells (MDSCs and M2 macrophages) in the tumor microenvironment, surpassing the therapeutic efficacies of approved live‐BCG drug and mRNA vaccine. The increase in CCR8+Foxp3+ Treg cells induced to counteract RSnP treatment can be attenuated by anti‐CCR8 antibody, a depletion antibody for tumor‐specific Treg cells, to synergize therapeutic efficacy with relieved autoimmunity. RSnP can be a therapeutic nanomedicine platform across heterologous cancers and emerging infectious virus variants with minimized toxicity.

A case with recurrent idiopathic anaphylaxis episodes starting soon after COVID-19 mRNA vaccination

Introduction: A patient was presented with a history of idiopathic recurrent anaphylaxis after administration of Pfizer BioNTech mRNA vaccine, and the attacks were controlled with omalizumab. To our knowledge, this is the first reported case of recurrent idiopathic anaphylaxis (IA) after administration of Pfizer BioNTech mRNA vaccine. Case Presentation: A 52-year-old man with recurrent episodes of IA after COVID-19 vaccination presented to our adult Allergy and Immunology Clinic. In the patient, urticaria and anaphylaxis episodes could not be controlled with high-dose antihistamine and systemic steroid treatment, and complete control was achieved with omalizumab treatment and anaphylaxis attacks completely regressed. Conclusion: In cases of unexplained or recurrent anaphylaxis in adult patients, COVID-19 vaccination and timing should be questioned, and its association with anaphylaxis might be considered.

Bridging One Health: Computational design of a multi-epitope messenger RNA vaccine for cross-species immunization against Nipah virus

Background and Aim: Nipah virus (NiV) poses a threat to human and animal health, particularly swine, which serve as primary vectors for human transmission. Despite its severe risks, no NiV vaccine currently exists for humans or animal hosts; thus, innovative vaccine development approaches that address cross-species transmission are required. This study was computationally designed to evaluate a multi-epitope messenger RNA (mRNA) vaccine targeting NiV for human and swine immunization. Materials and Methods: B and T lymphocyte epitopes were identified from NiV structural proteins using multiple epitope prediction tools. All epitopes were linked to form a multi-epitope construct, and various adjuvant combinations were analyzed for physicochemical properties and immune simulation. Molecular docking and dynamics were employed to visualize the construct’s interaction with a host immune receptor. Signal peptides were added to the construct, and mRNA sequences were generated using LinearDesign. The minimum free energies (MFEs) and codon adaptation indices (CAI) were used to select the final mRNA sequence of the vaccine construct. Results: Computational tools predicted 10 epitopes within NiV structural proteins that can be recognized by human and swine immune receptors. The construct with β-defensin 2 adjuvant was selected as the final immunogenic region after showing favorable immunogenicity profiles and physicochemical properties. The final vaccine sequence had higher MFE and CAI compared to the BioNTech/Pfizer BNT162b2 and Moderna mRNA-1273 vaccines. Conclusion: The multi-epitope mRNA vaccine designed in this study shows promising results as a potential NiV vaccine candidate. Further in vivo and in vitro studies are required to confirm the efficacy. Keywords: computational design, cross-species immunization, messenger RNA vaccine, multi-epitope, Nipah virus.

Single-chain A35R-M1R-B6R trivalent mRNA vaccines protect mice against both mpox virus and vaccinia virus

Mpox has spread to many countries around the world. While the existing live attenuated mpox vaccines are effective, advances in 21st century technologies now enable the development of vaccines with more specific antigens, clearer mechanisms, and more controllable side effects. We systematically evaluated the immunogenicity and protective efficacy of the A35R, M1R and B6R antigens of the mpox virus (MPXV). With these findings, we designed three single-chain trivalent mRNA vaccines (AMAB-wt, AMAB-C140S and AMB-C140S) by integrating the soluble regions of these antigens into single mRNA-encoded polypeptides based on their protein structures. Then, the immunogenicity and protective efficacy of these single-chain mRNA vaccines were evaluated in mice models against both VACV and MPXV. The three single-chain vaccines elicited neutralising antibodies that effectively neutralised both VACV and MPXV. The single-chain vaccines or cocktail vaccine containing mRNAs encoding soluble antigen (sA35R+sM1R+sB6R) exhibited 100% or 80% protection against a lethal dose of VACV challenge, while the cocktail of full-length antigens (A35+ M1+ B6) and the live attenuated vaccine, VACV Tian Tan (VACV-VTT), completely failed to protect mice. Moreover, the single-chain vaccines significantly reduced viral load in the lungs and ovaries of MPXV-challenged mice. Compared with the cocktail vaccines, our single-chain designs demonstrated similar or superior immunogenicity and protective efficacy. Importantly, the simplicity of the single-chain vaccines enhances both the controllability and accessibility of mpox vaccines. We believe these single-chain vaccines qualify as the next-generation mpox vaccines. National Natural Science Foundation of China and Youth Innovation Promotion Association of the CAS.

Healthcare utilization among COVID-19 mRNA vaccine-associated myocarditis cases: a matched retrospective cohort study.

We evaluated all-cause healthcare utilization among those with vaccine-associated myocarditis, compared to vaccinees without post-vaccination myocarditis. We conducted a retrospective cohort study in individuals aged 12 and older who received COVID-19 mRNA vaccination in British Columbia. Exposure was defined as an ED visit or hospitalization for myocarditis within 21 days post-vaccination. The primary outcome was healthcare utilization. Ratios of rate ratios (RRRs) for exposure-associated healthcare utilization were calculated using a difference-in-differences (DiD) analysis. In the post-index period, the exposed and unexposed groups showed substantial utilization rate difference (RD = 15.30 [95% CI, 14.47-16.13). A 51% overall increase in healthcare utilization was observed over 18 months among exposed individuals (RRR, 1.51 [95%CI, 1.08-2.11]). In the initial six months, healthcare utilization surpassed the 18-month estimate, exhibiting a 125% increase (RRR, 2.25 [95%CI, 1.43-3.52]), while the last 12 months showed no statistically significant change (RRR, 1.03 [95%CI, 0.72-1.47]). An additional 9.1 (95%CI, 8.53-9.71) visits per person were attributed to vaccine-associated myocarditis over 18 months (total excess = 938.26 healthcare visits). The initial surge in healthcare visits post-exposure, mainly outpatient follow-ups, followed by a return to baseline rates, indicates a positive prognosis and supports the vaccine's safety profile.

Advances in mRNA vaccine research in the field of quality control

Advances in mRNA vaccine research in the field of quality control

First bipolar episode following booster dose of COVID-19 vaccination

Introduction and importance: The interactions between the susceptibility of the host and some of the COVID-19 vaccine components happened. Viral infections, including COVID-19, are related to the pathogenesis of bipolar disorder (BD). These findings could trigger an initial bipolar episode. Case presentation: A 48-year-old Syrian married female, presented to the out-clinic of Modern Medical Centre Hospital, in July 2022 for episodes of sub-maniac/mania episodes, which began within 15 days after the booster dose of COVID-19 vaccination, preceded by depressive mood. Both family and personal past psychiatric and/or trauma history were negatives. Initiation of carbamazepine 600 mg/day showed significant improvement within 3 days; 3 months later, carbamazepine dose was decreased to 200 mg/day, as there were no clinical symptoms. Clinical discussion: mRNA vaccines of COVID-19 increase the levels of type I interferon (INF), an inflammatory cytokine that creates a signal leading to the expression of interleukins, INF, and tumor necrosis factor-alpha. The pathology of BD is also unclear. Genetic predisposition, immunological effects, and the classification of BD, itself, as an autoimmune disease play a role. Although rapid improvement following treatment, prolonged and maintenance treatment by essentially mood stabilizer should be considered in bipolar episodes initiated by COVID-19 vaccination. Rare data are available about maniac episodes after COVID-19 infection, but to our knowledge, we reported the first case of bipolar onset after the booster vaccination of COVID-19. Conclusion: Bipolar disease can present following a booster dose of COVID-19 vaccination in previously healthy people.

Features of influenza virus hemagglutinin genes and their recoding possibilities

The world has already entered the stage of increasing odds for a new pandemic, which prompts to seek out for new flu vaccines, because existing vaccines demonstrate only suboptimal effectiveness. With the Covid-19 pandemic, the possibility of using mRNA vaccines has been opened up, and a prospect of finding hemagglutinin (HA) gene mRNA-based new influenza vaccines seems very attractive. As a rule, the mRNA vaccine is a product of recoding, which ensures the mRNA stability. However, the results of mRNA recoding can be ambiguous. The purpose of this report is to analyze the features of genes and proteins and to consider opportunities and limitations in their recoding. Primary structures of NA proteins and relevant genes were retrieved from Internet publicly available databases. The amino acid composition and frequency of dipeptides, nucleotide and dinucleotide compositions, %GC, translational code and compositions of neighboring di- and tricodones, distribution along primary structure for explicit and synonymous mutations were determined. H1N1 and H3N2 subtypes have both specific and general features (limitations) in their genes, differing not only in the number of protein substitutions, but also in the number and distribution of gene synonymous codons, which do not manifest in the protein primary structure, but appear, apparently, as a hidden factor, which causes the low effectiveness of classical influenza vaccines. The identification of several limitations in gene structure suggests that its any modification (in any gene) must not contradict each of the restrictions established by nature. The frequency of CpG dinucleotides in all studied strains is low, but a potential for optimizing it in H1N1 strains due to the prohibition of the quartet in the gene for arginine-encoding codons is especially limited and can be implemented through synonymous codons of other amino acids (alanine, proline, threonine or serine). Compared to the H1N1 subtype, the H3N2 subtype can be expected to have more possibilities in constructing stable NA gene mRNA.

Acute tubulointerstitial nephritis following coronavirus disease 2019 mRNA vaccination: a pediatric case report.

Coronavirus disease 2019 (COVID-19) mRNA vaccines have been linked to various kidney adverse events including acute tubulointerstitial nephritis (ATIN). This report describes a 15-year-old female who developed persistent fever and fatigue 54days after receiving her second dose of the BNT162b2 2 SARS-CoV-2 vaccine. She presented with elevated serum creatinine and urinary β2-microglobulin (β2MG) levels. Kidney biopsy revealed mononuclear infiltrate with some eosinophils, confirming the diagnosis of ATIN. Repeatedly positive lymphocyte transformation test results for the vaccine suggested a relationship between the vaccine and interstitial nephritis. Initially, treatment with prednisolone was effective. However, an increase in urinary β2MG level was observed 7months later, and the introduction of mycophenolate mofetil (MMF) allowed for the gradual reduction and eventual cessation of prednisolone. This case represents one of the rare pediatric instances of ATIN following COVID-19 vaccination. MMF can be an effective alternative in corticosteroid-dependent cases.

STAR LIGHT Study: XBB.1.5 COVID-19 mRNA Vaccines Boost Systemic but Not Mucosal Immunity Against the SARS-CoV-2 JN.1 Variant in Patients with Chronic Liver Disease

Background: Patients with chronic liver disease (CLD) have impaired vaccine immunogenicity and an excess risk of severe COVID-19. While variant-adapted COVID-19 mRNA vaccines are recommended for vulnerable individuals, their efficacy in patients with CLD has not been studied. Methods: We present the first evaluation of XBB.1.5 COVID-19 vaccine immunogenicity against the SARS-CoV-2 JN.1 variant in patients with CLD. Serum anti-receptor binding domain (RBD) IgG, neutralization, and saliva anti-RBD IgG and IgA against wild-type SARS-CoV-2 (WT) and the XBB.1.5, EG.5.1, BA.2.86, and JN.1 variants were quantified before and 2–4 weeks following a fourth dose of XBB.1.5 mRNA vaccines. Results: Vaccination boosted anti-RBD IgG and neutralization against all tested variants including JN.1 (each p < 0.001). Following immunization, neutralization was lower against JN.1 compared to WT, XBB.1.5, and EG.5.1 (p < 0.001, p < 0.001, and p < 0.01, respectively). Vaccination reduced neutralization failure rates against BA.2.86 and JN.1 (each p < 0.05). The evasion of vaccine-induced antibodies by the tested variants was low, indicated by the positive correlation between anti-RBD IgG and neutralization. At mucosal sites, vaccination boosted anti-RBD IgG (each p < 0.01) but failed to induce infection-blocking IgA (each p > 0.05). Conclusion: XBB.1.5 vaccines protect CLD patients against recent SARS-CoV-2 variants, but developing vaccines with optimized mucosal immunogenicity is required to prevent SARS-CoV-2 transmission and recurrent seasonal COVID-19 outbreaks.

Determinants of protective humoral response to mRNA-1273 and BNT162b2 vaccines in peritoneal dialysis patients: a prospective cohort study

Patients with chronic kidney disease (CKD) on dialysis have a higher mortality rate associated with SARS-CoV-2 infection. Although vaccines are now available, the protective response rates and determinants of humoral response to the vaccine are poorly described in patients on peritoneal dialysis. This was a prospective observational study describing the response rates of detectable and standardized protective antibody titers one month after each mRNA vaccine dose in a cohort of 88 patients on peritoneal dialysis. We found that the vast majority of patients produced protective levels of antibodies (73%) one month after the second vaccine dose. In the multivariate analysis, the single determinant for an adequate humoral response was the weekly Kt/V, a surrogate of dialysis dose. The response rate was higher, but not significantly, with the mRNA-1273 than with the BNT162b2 vaccine one month after the second dose (78.7 vs. 46.2%, respectively, p = 0.02). We found that patients on peritoneal dialysis had a satisfactory humoral response rate, which was much higher than in transplant recipients. PD patients with a poor humoral response, particularly those with a low wKT/V, may benefit from an additional dose of vaccine.

Enhanced Broad-Spectrum Efficacy of an L2-Based mRNA Vaccine Targeting HPV Types 6, 11, 16, 18, with Cross-Protection Against Multiple Additional High-Risk Types

Background: Current L1-based human papillomavirus (HPV) vaccines provide type-specific protection but offer limited cross-protection against non-vaccine HPV types. Therefore, developing a broad-spectrum HPV vaccine is highly desirable. Methods: In this study, we optimized mRNA constructs and developed a multivalent L2-based mRNA vaccine encoding L2 aa 2-130, which includes all known neutralizing epitopes from four prevalent HPV types (HPV-6, -11, -16, and -18). We evaluated its immunogenicity in a mouse model and compared the efficacy of a commercially available mRNA delivery reagent with a custom-synthesized lipid nanoparticle (LNP) formulation. Results: We identified that a construct containing E01 (a 5′-untranslated region) and SL2.7 (a poly(A) polymerase recruitment sequence) significantly increased protein expression. The L2-based mRNA vaccine induced robust and long-lasting humoral immune responses, with significant titers of cross-reactive serum IgG antibodies against L2 epitopes. Notably, the vaccine elicited cross-neutralizing antibodies and conferred cross-protective immunity not only against vaccine-targeted HPV types but also against non-vaccine HPV types, following intravaginal challenge in mice. We also found that LNP delivered mRNA more effectively in vivo. Conclusions: The L2-based mRNA vaccine developed in this study shows significant potential for broad-spectrum protection against multiple HPV types. This approach offers a promising strategy for reducing the global burden of HPV-associated cancers.

Current Advance and Future of mRNA Vaccine in Cancer Therapy

After years of development, cancer vaccines have gradually become an important part of tumor immunotherapy, and have shown a more rapid development momentum under the background of the current era. The vaccine has the advantages of high efficiency, safety, rapid development potential, cost-effectiveness, etc. In recent years, with the continuous improvement of mRNA technology, relevant technologies in the field of mRNA molecules have also made breakthrough progress, and mRNA vaccines have achieved certain results in cancer treatment. Compared with traditional vaccines, mRNA vaccines can induce the body to produce humoral immunity and cellular immunity at the same time, and the research and development cycle is short, the cost is low, and it can quickly develop candidate vaccines to deal with virus mutation, which is conducive to cancer control. mRNA vaccines have become a current research hotspot and have wide application prospects in the prevention and treatment of tumors and infectious diseases. This article comprehensively discusses the structural characteristics, types, unique advantages and future prospects of mRNA vaccines, in order to help understand the vaccine function and clinical application of mRNA, provide a direction for the development of mRNA drugs, and expect that mRNA cancer vaccines will be used in clinic as soon as possible to benefit patients.

XBB.1.5-Adapted COVID-19 mRNA Vaccines but Not Infections With Previous Omicron Variants Boost Neutralisation Against the SARS-CoV-2 JN.1 Variant in Patients With Inflammatory Bowel Disease.

Variant-adapted COVID-19 vaccines are recommended for patients with inflammatory bowel disease (IBD). However, many patients rely on pre-existing immunity by original vaccines or prior infections. To assess whether such immunity sufficiently combats the highly immune-evasive SARS-CoV-2 JN.1 variant. Utilising two longitudinal cohorts, we evaluated immunity against JN.1 induced by original vaccines (IBD: n = 98; healthy: n = 48), omicron breakthrough infection (IBD: n = 55; healthy: n = 57) or XBB.1.5-adapted vaccines (IBD: n = 18). Neutralisation and anti-receptor-binding domain (RBD) IgG levels against wild-type SARS-CoV-2 and JN.1 were assessed using multiplex immunoassays. Study outcomes were wild-type and JN.1 neutralisation following three doses of original mRNA vaccines, stratified by immunosuppressive therapy (primary outcome), and JN.1 neutralisation following third-dose breakthrough infection or a fourth dose of XBB.1.5-adapted mRNA vaccines (secondary outcomes). Following original vaccines, JN.1 neutralisation was lower than wild-type neutralisation in all study groups (healthy, anti-TNF and non-anti-TNF; each p < 0.001); most individuals lacked JN.1 neutralisation (healthy: 97.9%; anti-TNF: 98.3% and non-anti-TNF: 92.3%). Confounder-adjusted multivariable modelling strongly associated anti-TNF therapy with low levels of anti-JN.1-RBD IgG (fold-change 0.48 [95% CI 0.39-0.59]). JN.1 neutralisation was similar in patients with or without breakthrough infection (anti-TNF, non-anti-TNF; each p > 0.05); neutralisation failure was 100% despite breakthrough infection. XBB.1.5-adapted vaccines enhanced JN.1 neutralisation (p < 0.001) and reduced neutralisation failure rates in patients with IBD (94.4% pre-vaccination vs. 44.4% post-vaccination; p = 0.003). Only variant-adapted vaccines protect against emerging SARS-CoV-2 variants. Patients with IBD and healthy individuals without recent vaccination may lack protection against the JN.1 subvariant KP.3 which causes current COVID-19 surges.

MRNA Vaccines: a Powerful Tool in Cancer Treatment

Cancer has always been one of the difficult objects for people to conquer. It’s killed a lot of people over a long period of time. As time goes on, technology becomes more and more advanced, and people are not limited to previous cancer treatments, but continue to research and try to find more treatments. In recent years, mRNA vaccines have gradually entered our field of vision. Compared with conventional vaccines, it often has a more flexible structure that can be modified, safer delivery methods, and higher efficiency. Although functional beyond imagination, the lack of knowledge in this area has prevented the use of mRNA vaccines in the treatment of many cancers. Once the many limitations and problems of mRNA are successfully solved, it can not only greatly promote the development of cancer treatment, but also make modern medicine get a milestone. This review introduces the current research and development progress of mRNA vaccines, and discusses the structure, delivery and application of mRNA vaccines.

Scientific and Regulatory Lessons Learnt on Building a Chemistry, Manufacturing, and Controls (CMC) Package for COVID-19 Variant Vaccine Updates in the EU—A Regulator’s Perspective

During the COVID-19 pandemic, eight COVID-19 vaccines were authorised in the European Union (EU); as a result of emerging SARS-CoV-2 variants and waning immunity, some of these have been adapted to broaden the immunity against circulating variants. The pace at which variants emerge challenges the technical feasibility to make adapted vaccines available in a suitable timeframe and in sufficient quantities. Despite the current absence of a clear-cut seasonal spread for COVID-19, the EU regulatory approach thus far is a pragmatic approach following a pathway similar to that of seasonal influenza. This approach currently requires chemistry, manufacturing, and controls (CMC—the design, development and consistent manufacture of a specified medicinal product of good quality) and non-clinical data (from product laboratory and animal studies), as well as demonstrating that updated vaccines induce an immune response that can predict clinical efficacy and safety in humans. For CMC data, COVID-19 mRNA vaccine adaptations generally made use of the same formulation, control strategy, manufacturing process, and inclusion of registered manufacturing sites for the drug product; therefore assessment was generally streamlined. The experience gained from the vaccine adaptations, combined with a continuous early regulator-developer scientific discussion, permits increasingly greater predictability for timing and positive regulatory outcomes. Here, we review key aspects of the quality control and manufacture of updating COVID-19 vaccines to protect against new variants. Although most experience has been gained with mRNA vaccines, we note that investment in the streamlining of manufacturing processes for recombinant protein vaccines would facilitate future strain updates/adaptations thereby safeguarding availability of different COVID-19 vaccine types, which is considered of value for public health. We also reflect on the challenges and opportunities in establishing more predictable regulatory mechanisms for future COVID-19 vaccine adaptions and more widely for future vaccines containing rapidly evolving pathogens with the potential to cause health threats.