Comparison of the effectiveness four years after Homo/Hetero prime-boost with 10 µg HP and 20 µg CHO recombinant hepatitis B vaccine at 1 and 6 months in maternal HBsAg-negative children.

Introduction: Limited data were available on the effectivenessfour years after Homo or Hetero prime-boost with 10 µg Hansenulapolymorpha recombinant hepatitis B vaccine (HepB-HP) and 20 µgChinese hamster ovary cell HepB (HepB-CHO). Methods: A crosssectional study was performed in maternalhepatitis B surface antigen (HBsAg)-negative children whoreceived one dose of 10 µg HepB-HP at birth, Homo or Heteroprime-boost with 10 µg HepB-HP and 20 µg HepB-CHO at 1 and 6months. HBsAg and hepatitis B surface antibody (anti-HBs) fouryears after immunization were quantitatively detected by achemiluminescent microparticle immunoassay (CMIA). Results: A total of 359 children were included; 119 childrenreceived two doses of 10 µg HepB-HP and 120 children receivedtwo doses of 20 µg HepB-CHO, called Homo prime-boost; 120children received Hetero prime-boost with 10 µg HepB-HP and 20µg HepB-CHO. All children were HBsAg negative. The geometricmean concentration (GMC) and overall seropositivity rate (SPR) ofanti-HBs were 59.47 (95%CI: 49.00 - 72.16) mIU/ml and 85.51%(307/359). Nearly 15% of the study subjects had an anti-HBsconcentration < 10 mIU/ml and 5.01% had an anti-HBsconcentration ≤ 2.5 mIU/ml. The GMC of the 20 µg CHO Homoprime-boost group [76.05 (95%CI: 54.97 - 105.19) mIU/ml] washigher than that of the 10 µg HP Homo group [45.86 (95%CI:31.94 - 65.84) mIU/ml] (p = 0.035). The GMCs of the Heteroprime-boost groups (10 µg HP-20 µg CHO and 20 µg CHO-10 µgHP) were 75.86 (95% CI: 48.98 - 107.15) mIU/ml and 43.65(95%CI: 27.54 - 69.18) mIU/ml, respectively (p = 0.041). Aftercontrolling for sex influence, the SPR of the 20 µg CHO Homoprime-boost group was 2.087 times than that of the 10 µg HPHomo group. Discussion: The HepB booster was not necessary in the generalchildren, Homo/Hetero prime-boost with 20 µg HepB-CHO wouldincrease the anti-HBs concentration four years after immunization,timely testing and improved knowledge about the self-pay vaccinewould be good for controlling hepatitis B.

Immunogenicity and safety of live attenuated and recombinant/inactivated varicella zoster vaccines in people living with HIV: A systematic review.

Few papers focus their attention on VZV vaccination effectiveness among people living with HIV (PLWH). Flanking the live attenuated vaccine (VZL) available, a newly recombinant vaccine (RZV) was recently introduced and approved for HZ prevention among adults. PLWH represents a population on which a particular attention should be applied, in order to guarantee the vaccine efficacy and safety. We performed a literature search in USNLM, PubMed, PubMed Central, PMC and Cochrane Library. From all the publications found eligible, data were extracted and processed per population, vaccine type, immunogenicity and ADRs. The review of the 13 included studies shows that both RZV and VZL are immunogenic and have an acceptable safety profile in adults and children living with HIV. However, given the lack of research available about vaccine efficacy in preventing VZV and HZ in PLWH, additional studies need to be performed, in order to achieve a full completeness of data.

Recombinant parainfluenza virus 5 expressing clade 2.3.4.4b H5 hemagglutinin protein confers broad protection against H5Ny influenza viruses.

The global circulation of clade 2.3.4.4b H5Ny highly pathogenic avian influenza viruses (HPAIVs) in poultry and wild birds, increasing mammal infections, continues to pose a public health threat and may even form a pandemic. An efficacious vaccine against H5Ny HPAIVs is crucial for emergency use and pandemic preparedness. In this study, we developed a parainfluenza virus 5 (PIV5)-based vaccine candidate expressing hemagglutinin (HA) protein of clade 2.3.4.4b H5 HPAIV, termed rPIV5-H5, and evaluated its safety and efficacy in mice and ferrets. Our results demonstrated that intranasal immunization with a single dose of rPIV5-H5 could stimulate H5-specific antibody responses, moreover, a prime-boost regimen using rPIV5-H5 stimulated robust humoral, cellular, and mucosal immune responses in mice. Challenge study showed that rPIV5-H5 prime-boost regimen provided sterile immunity against lethal clade 2.3.4.4b H5N1 virus infection in mice and ferrets. Notably, rPIV5-H5 prime-boost regimen provided protection in mice against challenge with lethal doses of heterologous clades 2.2, 2.3.2, and 2.3.4 H5N1, and clade 2.3.4.4h H5N6 viruses. These results revealed that rPIV5-H5 can elicit protective immunity against a diverse clade of highly pathogenic H5Ny virus infection in mammals, highlighting the potential of rPIV5-H5 as a pan-H5 influenza vaccine candidate for emergency use.IMPORTANCEClade 2.3.4.4b H5Ny highly pathogenic avian influenza viruses (HPAIVs) have been widely circulating in wild birds and domestic poultry all over the world, leading to infections in mammals, including humans. Here, we developed a recombinant PIV5-vectored vaccine candidate expressing the HA protein of clade 2.3.4.4b H5 virus. Intranasal immunization with rPIV5-H5 in mice induced airway mucosal IgA responses, high levels of antibodies, and robust T-cell responses. Importantly, rPIV5-H5 conferred complete protection in mice and ferrets against clade 2.3.4.4b H5N1 virus challenge, the protective immunity was extended against heterologous H5Ny viruses. Taken together, our data demonstrate that rPIV5-H5 is a promising vaccine candidate against diverse H5Ny influenza viruses in mammals.

Comparative safety analysis of mRNA and adenoviral vector COVID-19 vaccines: a nationwide cohort study using an emulated target trial approach.

OBJECTIVE: This nationwide cohort study compared the incidence of adverse events of special interest (AESIs) between adenoviral vector-based (ChAdOx1) and mRNA-based (BNT162b2 or mRNA-1273) coronavirus disease 2019 (COVID-19) vaccines. METHODS: A targeted trial emulation study was conducted using data from the National Health Insurance Service database. Vaccinees aged 18-85 years who had received at least one dose of ChAdOx1 or an mRNA-based vaccine were identified. The 42-day risks of AESIs were calculated. RESULTS: A total of 1 767 539 ChAdOx1 vaccinees were matched exactly with mRNA vaccinees according to their risk factors. The 42-day risks of adverse events were low (∼0 to 176 events per 100 000 persons in both vaccine groups), and the incidence rates of AESIs were comparable between the two platforms, except for a higher occurrence of acute cardiac injury (incidence rate ratio [IRR], 1.22; 95% CI, 1.10-1.35), myocarditis or pericarditis (IRR, 2.14; 95% CI, 1.14-4.04), and arrhythmia (IRR, 1.46; 95% CI, 1.24-1.71) in mRNA vaccinees. The incidence of Guillain-Barré syndrome (IRR, 0.20; 95% CI, 0.06-0.69), vasovagal syncope (IRR, 0.77; 95% CI, 0.62-0.97), radiculopathy (IRR = 0.59, 95% CI, 0.41-0.84), and aseptic arthritis (IRR, 0.81; 95% CI, 0.70-0.93) was significantly lower in mRNA-based vaccinees compared with ChAdOx1 vaccinees. DISCUSSION: A remarkable platform-dependent difference was observed in the safety profiles of COVID-19 vaccines, particularly for myocarditis or pericarditis and Guillain-Barré syndrome. However, the overall risk of AESIs was low for both vaccine platforms.

Recombinant or Standard-Dose Influenza Vaccine in Adults under 65 Years of Age.

BACKGROUND: Quadrivalent recombinant influenza vaccines contain three times the amount of hemagglutinin protein as standard-dose egg-based vaccines, and the recombinant formulation is not susceptible to antigenic drift during manufacturing. Data are needed on the relative effectiveness of recombinant vaccines as compared with standard-dose vaccines against influenza-related outcomes in adults under the age of 65 years. METHODS: In this cluster-randomized observational study, Kaiser Permanente Northern California facilities routinely administered either a high-dose recombinant influenza vaccine (Flublok Quadrivalent) or one of two standard-dose influenza vaccines during the 2018-2019 and 2019-2020 influenza seasons to adults 50 to 64 years of age (primary age group) and 18 to 49 years of age. Each facility alternated weekly between the two vaccine formulations. The primary outcome was influenza (A or B) confirmed by polymerase-chain-reaction (PCR) testing. Secondary outcomes included influenza A, influenza B, and influenza-related hospitalization outcomes. We used Cox regression analysis to estimate the hazard ratio of the recombinant vaccine as compared with the standard-dose vaccines against each outcome. We calculated the relative vaccine effectiveness as 1 minus the hazard ratio. RESULTS: The study population included 1,630,328 vaccinees between the ages of 18 and 64 years (632,962 in the recombinant-vaccine group and 997,366 in the standard-dose group). During this study period, 1386 cases of PCR-confirmed influenza were diagnosed in the recombinant-vaccine group and 2435 cases in the standard-dose group. Among the participants who were 50 to 64 years of age, 559 participants (2.00 cases per 1000) tested positive for influenza in the recombinant-vaccine group as compared with 925 participants (2.34 cases per 1000) in the standard-dose group (relative vaccine effectiveness, 15.3%; 95% confidence interval [CI], 5.9 to 23.8; P = 0.002). In the same age group, the relative vaccine effectiveness against influenza A was 15.7% (95% CI, 6.0 to 24.5; P = 0.002). The recombinant vaccine was not significantly more protective against influenza-related hospitalization than were the standard-dose vaccines. CONCLUSIONS: The high-dose recombinant vaccine conferred more protection against PCR-confirmed influenza than an egg-based standard-dose vaccine among adults between the ages of 50 and 64 years. (Funded by Sanofi; ClinicalTrials.gov number, NCT03694392.).

SARS-CoV-2 Omicron Spike recognition by plasma from individuals receiving BNT162b2 mRNA vaccination with a 16-week interval between doses.

Continuous emergence of SARS-CoV-2 variants of concern (VOCs) is fueling the COVID-19 pandemic. Omicron (B.1.1.529) rapidly spread worldwide. The large number of mutations in its Spike raise concerns about a major antigenic drift that could significantly decrease vaccine efficacy and infection-induced immunity. A long interval between BNT162b2 mRNA doses elicits antibodies that efficiently recognize Spikes from different VOCs. Here, we evaluate the recognition of Omicron Spike by plasma from a cohort of SARS-CoV-2 naive and previously infected individuals who received their BNT162b2 mRNA vaccine 16 weeks apart. Omicron Spike is recognized less efficiently than D614G, Alpha, Beta, Gamma, and Delta Spikes. We compare with plasma activity from participants receiving a short (4 weeks) interval regimen. Plasma from individuals of the long-interval cohort recognize and neutralize better the Omicron Spike compared with those who received a short interval. Whether this difference confers any clinical benefit against Omicron remains unknown.

Herpes zoster: A Review of Clinical Manifestations and Management.

The Varicella-zoster virus (VZV) or human herpes virus 3 is a neurotropic human alpha herpes virus responsible for chickenpox/varicella and shingles/Herpes zoster (HZ). This review will focus on HZ. Since HZ is secondary to varicella, its incidence increases with age. In children and youngsters, HZ is rare and associated to metabolic and neoplastic disorders. In adults, advanced age, distress, other infections (such as AIDS or COVID-19), and immunosuppression are the most common risk factors. HZ reactivation has recently been observed after COVID-19 vaccination. The disease shows different clinical stages of variable clinical manifestations. Some of the manifestations bear a higher risk of complications. Among the possible complications, postherpetic neuralgia, a chronic pain disease, is one of the most frequent. HZ vasculitis is associated with morbidity and mortality. Renal and gastrointestinal complications have been reported. The cornerstone of treatment is early intervention with acyclovir or brivudine. Second-line treatments are available. Pain management is essential. For (secondary) prophylaxis, currently two HZV vaccines are available for healthy older adults, a live attenuated VZV vaccine and a recombinant adjuvanted VZV glycoprotein E subunit vaccine. The latter allows vaccination also in severely immunosuppressed patients. This review focuses on manifestations of HZ and its management. Although several articles have been published on HZ, the literature continues to evolve, especially in regard to patients with comorbidities and immunocompromised patients. VZV reactivation has also emerged as an important point of discussion during the COVID-19 pandemic, especially after vaccination. The objective of this review is to discuss current updates related to clinical presentations, complications, and management of HZ.

A Novel Recombinant FAdV-4 Virus with Fiber of FAdV-8b Provides Efficient Protection against Both FAdV-4 and FAdV-8b.

Since 2015, the outbreaks of hydropericardium-hepatitis syndrome (HHS) and inclusion body hepatitis (IBH) caused by the highly pathogenic serotype 4 fowl adenovirus (FAdV-4) and serotype 8 fowl adenovirus (FAdV-8), respectively, have caused huge economic losses to the poultry industry. Although several vaccines have been developed to control HHS or IBH, a recombinant genetic engineering vaccine against both FAdV-4 and FAdV-8 has not been reported. In this study, recombinant FAdV-4 expressing the fiber of FAdV-8b, designated as FA4-F8b, expressing fiber of FAdV-8b was generated by the CRISPR-Cas9 and homologous recombinant techniques. Infection studies in vitro and in vivo revealed that the FA4-F8b replicated efficiently in LMH cells and was also highly pathogenic to 2-week-old SPF chickens. Moreover, the inoculation of inactivated the FA4-F8b in chickens could not only induce highly neutralizing antibodies, but also provide efficient protection against both FAdV-4 and FAdV-8b. All these demonstrate that the inactivated recombinant FA4-F8b generated here can act as a vaccine candidate to control HHS and IBH, and FAdV-4 can be an efficient vaccine vector to deliver foreign antigens.

Immune responses following the first dose of the Sputnik V (Gam-COVID-Vac).

As the first dose of Gam-COVID-Vac, is currently used as a single dose vaccine in some countries, we investigated the immunogenicity of this at 4 weeks (327 naïve individuals). 88.7% seroconverted, with significantly lower seroconversion rates in those over 60 years (p = 0.004) and significantly lower than previously seen with AZD1222 (p = 0.018). 82.6% developed ACE2 receptor blocking antibodies, although levels were significantly lower than following natural infection (p = 0.0009) and a single dose of AZD1222 (p < 0.0001). Similar titres of antibodies were observed to the receptor binding domain of WT, B.1.1.7 and B.1.617.2 compared to AZD1222, while the levels for B.1.351 were significantly higher (p = 0.006) for Gam-COVID-Vac. 30% developed ex vivo IFNγ ELISpot responses (significantly lower than AZD1222), and high frequency of CD107a expressing T cells along with memory B cell responses. Although single dose of Gam-COVID-Vac was highly immunogenic, administration of a second dose is likely to be beneficial.

Opportunities and Challenges for mRNA Delivery Nanoplatforms.

With the global outbreak of SARS-CoV-2, mRNA vaccines became the first type of COVID-19 vaccines to enter clinical trials because of their facile production, low cost, and relative safety, which initiated great advances in mRNA therapeutic techniques. However, the development of mRNA therapeutic techniques still confronts some challenges. First, in vitro transcribed mRNA molecules can be easily degraded by ribonuclease (RNase), resulting in their low stability. Next, the negative charge of mRNA molecules prevents them from direct cell entry. Therefore, finding efficient and safe delivery technology could be the key issue to improve mRNA therapeutic techniques. In this Perspective, we mainly discuss the problems of the existing mRNA-based delivery nanoplatforms, including safety evaluation, administration routes, and preparation technology. Moreover, we also propose some views on strategies to further improve mRNA delivery technology.

Reactogenicity among health care workers following a BNT162b2 or mRNA-1273 second dose after priming with a ChAdOx1 nCOV-19 vaccine.

OBJECTIVES: In March 2021, French authorities recommended a heterologous second dose of the mRNA vaccine for persons aged <55 years, with administration 9 to 12 weeks after the first dose of ChAdOx1 nCoV-19. This recommendation was despite a lack of data on the reactogenicity and safety of the regimen. Since then, several studies have shown an acceptable short-term safety profile of ChAdOx1 nCoV-19 and BNT162b2 heterologous vaccination, although some transient increased reactogenicity has been described. METHODS: We performed a single-centre prospective observational cohort study among health care workers (HCWs) at a tertiary care hospital to assess the reactogenicity of the BNT162b2 and mRNA-1273 vaccines administered as a second dose in participants primed with ChAdOx1 nCoV-19. RESULTS: Among 1184 HCWs, 356 (30%) agreed to participate. Of the participants, 32.3% were male, and the mean age was 35 years (standard deviation: 10.1 years). Of the participants, 229 received BNT162b2 and 127 received mRNA-1273. A systemic reaction was observed in 130 of 229 (56.8%) and 100 of 127 (78.7%) HCWs, respectively. Injection site reactions were generally limited (grade 1 or 2 in 163 of 229 (97.6%) and 90 of 127 (85.7 %) HCWs, respectively). After adjustment for age, sex, and HCW role, receiving the mRNA-1273 vaccine was associated with higher reactogenicity with more grade 3 side effects (adjusted OR (aOR): 3.34; 95% CI, 1.91-5.85), more systemic symptoms (aOR: 2.82; 95% CI, 1.69-4.7), and not being able to work (aOR: 8.35; 95% CI, 3.78-18.44) compared with receiving the BNT162b2 vaccine. DISCUSSION: Among patients receiving the mRNA1273 vaccine as a second dose, our study confirms good tolerance of the heterologous schedule with a higher risk of short-term side effects in comparison with patients receiving the BNT162b2 vaccine.

SARS-CoV-2 mRNA vaccine induces robust specific and cross-reactive IgG and unequal neutralizing antibodies in naive and previously infected people.

Understanding vaccine-mediated protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is critical to overcoming the global coronavirus disease 2019 (COVID-19) pandemic. We investigate mRNA-vaccine-induced antibody responses against the reference strain, seven variants, and seasonal coronaviruses in 168 healthy individuals at three time points: before vaccination, after the first dose, and after the second dose. Following complete vaccination, both naive and previously infected individuals developed comparably robust SARS-CoV-2 spike antibodies and variable levels of cross-reactive antibodies to seasonal coronaviruses. However, the strength and frequency of SARS-CoV-2 neutralizing antibodies in naive individuals were lower than in previously infected individuals. After the first vaccine dose, one-third of previously infected individuals lacked neutralizing antibodies; this was improved to one-fifth after the second dose. In all individuals, neutralizing antibody responses against the Alpha and Delta variants were weaker than against the reference strain. Our findings support future tailored vaccination strategies against emerging SARS-CoV-2 variants as mRNA-vaccine-induced neutralizing antibodies are highly variable among individuals.

Delivery Strategies for mRNA Vaccines.

The therapeutic potential for messenger RNA (mRNA) in infectious diseases and cancer was first realized almost three decades ago, but only in 2018 did the first lipid nanoparticle-based small interfering RNA (siRNA) therapy reach the market with the United States Food and Drug Administration (FDA) approval of patisiran (Onpattro™) for hereditary ATTR amyloidosis. This was largely made possible by major advances in the formulation technology for stabilized lipid-based nanoparticles (LNPs). Design of the cationic ionizable lipids, which are a key component of the LNP formulations, with an acid dissociation constant (pKa) close to the early endosomal pH, would not only ensure effective encapsulation of mRNA into the stabilized lipoplexes within the LNPs, but also its subsequent endosomal release into the cytoplasm after endocytosis. Unlike other gene therapy modalities, which require nuclear delivery, the site of action for exogenous mRNA vaccines is the cytosol where they get translated into antigenic proteins and thereby elicit an immune response. LNPs also protect the mRNA against enzymatic degradation by the omnipresent ribonucleases (RNases). Cationic nano emulsion (CNE) is also explored as an alternative and relatively thermostable mRNA vaccine delivery vehicle. In this review, we have summarized the various delivery strategies explored for mRNA vaccines, including naked mRNA injection; ex vivo loading of dendritic cells; CNE; cationic peptides; cationic polymers and finally the clinically successful COVID-19 LNP vaccines (Pfizer/BioNTech and Moderna vaccines)-their components, design principles, formulation parameter optimization and stabilization challenges. Despite the clinical success of LNP-mRNA vaccine formulations, there is a specific need to enhance their storage stability above 0 °C for these lifesaving vaccines to reach the developing world.

Development and utilization of a surrogate SARS-CoV-2 viral neutralization assay to assess mRNA vaccine responses.

BACKGROUND: Tests for SARS-CoV-2 immunity are needed to help assess responses to vaccination, which can be heterogeneous and may wane over time. The plaque reduction neutralization test (PRNT) is considered the gold standard for measuring serum neutralizing antibodies but requires high level biosafety, live viral cultures and days to complete. We hypothesized that competitive enzyme linked immunoassays (ELISAs) based on SARS-CoV-2 spike protein's receptor binding domain (RBD) attachment to its host receptor, the angiotensin converting enzyme 2 receptor (ACE2r), would correlate with PRNT, given the central role of RBD-ACE2r interactions in infection and published studies to date, and enable evaluation of vaccine responses. METHODS AND RESULTS: Configuration and development of a competitive ELISA with plate-bound RBD and soluble biotinylated ACE2r was accomplished using pairs of pre/post vaccine serum. When the competitive ELISA was used to evaluate N = 32 samples from COVID-19 patients previously tested by PRNT, excellent correlation in IC50 results were observed (rs = .83, p < 0.0001). When the competitive ELISA was used to evaluate N = 42 vaccinated individuals and an additional N = 13 unvaccinated recovered COVID-19 patients, significant differences in RBD-ACE2r inhibitory activity were associated with prior history of COVID-19 and type of vaccine received. In longitudinal analyses pre and up to 200 days post vaccine, surrogate neutralizing activity increased markedly after primary and booster vaccine doses, but fell substantially, up to <12% maximal levels within 6 months. CONCLUSIONS: A competitive ELISA based on inhibition of RBD-ACE2r attachment correlates well with PRNT, quantifies significantly higher activity among vaccine recipients with prior COVID (vs. those without), and highlights marked declines in surrogate neutralizing activity over a 6 month period post vaccination. The findings raise concern about the duration of vaccine responses and potential need for booster shots.

Development of a high-throughput platform for screening lipid nanoparticles for mRNA delivery.

mRNA lipid nanoparticles (LNPs) are at the forefront of nucleic acid intracellular delivery, as exemplified by the recent emergency approval of two mRNA LNP-based COVID-19 vaccines. The success of an LNP product largely depends on the systematic optimisation of the four lipidic components, namely the ionisable lipid, PEG lipid, structural and helper lipids. However, the in vitro screening of novel lipidic components and LNP compositions is limited by the low-throughput of LNP preparation. To address these issues, we herein present an automated high-throughput screening platform to select novel ionisable lipids and corresponding LNPs encapsulating mRNA in vitro. This high-throughput platform employs a lab-based automated liquid handling system, amenable to high-throughput (up to 384 formulations per plate and several plates per run) and allows precise mixing and reproducible mRNA LNP preparation which ensures a direct head-to-head comparison of hundreds and even thousands of novel LNPs. Most importantly, the robotic process has been successfully applied to the screening of novel LNPs encapsulating mRNA and has identified the same novel mRNA LNP leads as those from microfluidics-mixing technology, with a correlation coefficient of 0.8751. This high-throughput platform can facilitate to narrow down the number of novel ionisable lipids to be evaluated in vivo. Moreover, this platform has been integrated into a fully-automated workflow for LNP property control, physicochemical characterisation and biological evaluation. The high-throughput platform may accelerate proprietary lipid development, mRNA LNP lead optimisation and candidate selection to advance preclinical mRNA LNP development to meet urgent global needs.

Efficacy of mRNA, adenoviral vector, and perfusion protein COVID-19 vaccines.

Coronavirus disease 2019 (COVID-19) has a devastating impact on global populations triggered by a highly infectious viral sickness, produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The third major cause of mortality in the United States, following heart disease and cancer in 2020, was undoubtedly COVID-19. The centers for disease control and prevention (CDC) and the world health organization (WHO) separately developed a categorization system for differentiating new strains of SARS-CoV-2 into variants of concern (VoCs) and variants of interest (VoIs) with the continuing development of various strains SARS-CoV-2. By December 2021, five of the SARS-CoV-2 VoCs were discovered from the onset of the pandemic depending on the latest epidemiologic report by the WHO: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). Mutations in the receptor-binding domain (RBD) and n-terminal domain (NTD) have been found throughout all five identified VoCs. All strains other than the delta mutant are often found with the N501Y mutation situated on the RBD, resulting in higher binding between the spike protein and angiotensin-converting enzyme 2 (ACE2) receptors, enhanced viral adhesion, and following the entrance to host cells. The introduction of these new strains of SRAS-CoV-2 is likely to overcome the remarkable achievements gained in restricting this viral disease to the point where it is presented with remarkable vaccine developments against COVID-19 and strong worldwide mass immunization initiatives. Throughout this literature review, the effectiveness of current COVID-19 vaccines for managing and prohibiting SARS-CoV-2 strains is thoroughly described.

Revisiting the role of pulsed electric fields in overcoming the barriers to in vivo gene electrotransfer.

Gene therapies are revolutionizing medicine by providing a way to cure hitherto incurable diseases. The scientific and technological advances have enabled the first gene therapies to become clinically approved. In addition, with the ongoing COVID-19 pandemic, we are witnessing record speeds in the development and distribution of gene-based vaccines. For gene therapy to take effect, the therapeutic nucleic acids (RNA or DNA) need to overcome several barriers before they can execute their function of producing a protein or silencing a defective or overexpressing gene. This includes the barriers of the interstitium, the cell membrane, the cytoplasmic barriers and (in case of DNA) the nuclear envelope. Gene electrotransfer (GET), i.e., transfection by means of pulsed electric fields, is a non-viral technique that can overcome these barriers in a safe and effective manner. GET has reached the clinical stage of investigations where it is currently being evaluated for its therapeutic benefits across a wide variety of indications. In this review, we formalize our current understanding of GET from a biophysical perspective and critically discuss the mechanisms by which electric field can aid in overcoming the barriers. We also identify the gaps in knowledge that are hindering optimization of GET in vivo.

Chemically modified mRNA beyond COVID-19: Potential preventive and therapeutic applications for targeting chronic diseases.

Chemically modified mRNA represents a unique, efficient, and straightforward approach to produce a class of biopharmaceutical agents. It has been already approved as a vaccination-based method for targeting SARS-CoV-2 virus. The COVID-19 pandemic has highlighted the prospect of synthetic modified mRNA to efficiently and safely combat various diseases. Recently, various optimization advances have been adopted to overcome the limitations associated with conventional gene therapeutics leading to wide-ranging applications in different disease conditions. This review sheds light on emerging directions of chemically modified mRNAs to prevent and treat widespread chronic diseases, including metabolic disorders, cancer vaccination and immunotherapy, musculoskeletal disorders, respiratory conditions, cardiovascular diseases, and liver diseases.