The synthesis and preliminary immunological evaluation of a dual-adjuvant SARS-CoV-2 RBD vaccine: Covalent integration of TLR7/8 and iNKT cell agonists.

Covalently linking an adjuvant to an antigenic protein enhances its immunogenicity by ensuring a synergistic delivery to the immune system, fostering a more robust and targeted immune response. Most adjuvant-protein conjugate vaccines incorporate only one adjuvant due to the difficulties in its synthesis. However, there is a growing interest in developing vaccines with multiple adjuvants designed to elicit a more robust and targeted immune response by engaging different aspects of the immune system for complex diseases where traditional vaccines fall short. Here, we pioneer the synthesis of a dual-adjuvants protein conjugate Vaccine 1 by assembling a toll-like receptor 7/8 (TLR7/8) agonist, an invariant natural killer T cell (iNKT) agonist with a clickable bicyclononyne (BCN). The BCN group can bio-orthogonally react with azide-modified severe acute respiratory syndrome coronavirus-2 receptor-binding domain (SARS-CoV-2 RBD) trimer antigen to give the three-component Vaccine 1. Notably, with a mere 3 µg antigen, it elicited a balanced subclass of IgG titers and 20-fold more IgG2a than control vaccines, highlighting its potential for enhancing antibody-dependent cellular cytotoxicity. This strategy provides a practicable way to synthesize covalently linked dual immunostimulants. It expands the fully synthetic self-adjuvant protein vaccine that uses a single adjuvant to include two different types of adjuvants.

Recombinant Rod Domain of Vimentin Reduces SARS-CoV-2 Viral Replication by Blocking Spike Protein-ACE2 Interactions.

Although the SARS-CoV-2 vaccination is the primary preventive intervention, there are still few antiviral therapies available, with current drugs decreasing viral replication once the virus is intracellular. Adding novel drugs to target additional points in the viral life cycle is paramount in preventing future pandemics. The purpose of this study was to create and test a novel protein to decrease SARS-CoV-2 replication. We created the recombinant rod domain of vimentin (rhRod) in E. coli and used biolayer interferometry to measure its affinity to the SARS-CoV-2 S1S2 spike protein and the ability to block the SARS-CoV-2-ACE2 interaction. We performed plaque assays to measure rhRod's effect on SARS-CoV-2 replication in Vero E6 cells. Finally, we measured lung inflammation in SARS-CoV-2-exposed K18-hACE transgenic mice given intranasal and intraperitoneal rhRod. We found that rhRod has a high affinity for the S1S2 protein with a strong ability to block S1S2-ACE2 interactions. The daily addition of rhRod decreased viral replication in Vero E6 cells starting at 48 h at concentrations >1 µM. Finally, SARS-CoV-2-infected mice receiving rhRod had decreased lung inflammation compared to mock-treated animals. Based on our data, rhRod decreases SARS-CoV-2 replication in vitro and lung inflammation in vivo. Future studies will need to evaluate the protective effects of rhRod against additional viral variants and identify the optimal dosing scheme that both prevents viral replication and host lung injury.

The development and application of pseudoviruses: assessment of SARS-CoV-2 pseudoviruses.

Although most Coronavirus disease (COVID-19) patients can recover fully, the disease remains a significant cause of morbidity and mortality. In addition to the consequences of acute infection, a proportion of the population experiences long-term adverse effects associated with SARS-CoV-2. Therefore, it is still critical to comprehend the virus's characteristics and how it interacts with its host to develop effective drugs and vaccines against COVID-19. SARS-CoV-2 pseudovirus, a replication-deficient recombinant glycoprotein chimeric viral particle, enables investigations of highly pathogenic viruses to be conducted without the constraint of high-level biosafety facilities, considerably advancing virology and being extensively employed in the study of SARS-CoV-2. This review summarizes three methods of establishing SARS-CoV-2 pseudovirus and current knowledge in vaccine development, neutralizing antibody research, and antiviral drug screening, as well as recent progress in virus entry mechanism and susceptible cell screening. We also discuss the potential advantages and disadvantages.

A comprehensive review on the global efforts on vaccines and repurposed drugs for combating COVID-19.

The recently discovered coronavirus, known as SARS-CoV-2, is a highly contagious and potentially lethal viral infection that was declared a pandemic by the World Health Organization on March 11, 2020. Since the beginning of the pandemic, an unprecedented number of COVID-19 vaccine candidates have been investigated for their potential to manage the pandemic. Herein, we reviewed vaccine development and the associated research effort, both traditional and forward-looking, to demonstrate the advantages and disadvantages of their technology, in addition to their efficacy limitations against mutant SARS-CoV-2. Moreover, we report repurposed drug discovery, which mainly focuses on virus-based and host-based targets, as well as their inhibitors. SARS-CoV-2 targets include the main protease (Mpro), and RNA-dependent RNA-polymerase (RdRp), which are the most well-studied and conserved across coronaviruses, enabling the development of broad-spectrum inhibitors of these enzymes.

The impacts of the COVID-19 pandemic on patients with viral hepatitis B infection: follow-up, compliance with antiviral treatment, and vaccine preferences.

OBJECTIVE: Elimination programs and interventions for patients with viral hepatitis B (HBV) have been disrupted during the COVID-19 pandemic. This study aimed to evaluate the effects of the COVID-19 pandemic on patients with HBV infection in terms of COVID-19 vaccine preferences, follow-up visits, and antiviral treatment compliance. PATIENTS AND METHODS: In this retrospective single-center cross-sectional study, 129 patients with viral hepatitis B infection were evaluated. The patients were surveyed at the time of admission. A special form was created for patients with viral hepatitis B infection, and the form contained information about the patients at admission to collect the study data. RESULTS: A total of 129 participants were included in the study. Of the participants, 49.6% were males and the median age was 50 years. In total, 73 (56.6%) patients had their follow-up visits disrupted because of the COVID-19 pandemic. No newly diagnosed case of HBV infection was detected. Among the 129 patients, 46 had inactive hepatitis B, and 83 had chronic hepatitis B infection and were receiving antiviral treatment. None of the patients had trouble reaching antiviral treatments during the COVID-19 pandemic. A liver biopsy was recommended for 8 patients. Half of these 8 patients did not have follow-up visits during the COVID-19 pandemic. Most of the patients (123/129, 95.3%) received the COVID-19 vaccine and the most frequent vaccine that was used was the Pfizer-BioNTech (n: 92, 71.3%) vaccine. Serious side effects of the COVID-19 vaccines were not detected. Mild side effects were found in 41.9% (13/31) of the patients. The COVID antibody level was found to be statistically and significantly higher in the patients who received the Pfizer-BioNTech vaccine than in those that received the CoronoVac vaccine. CONCLUSIONS: It was reported that elimination programs and interventions for HBV infection decreased or stopped because of the COVID-19 pandemic. In the present study, no newly diagnosed case of HBV infection was detected. Most of the patients had their follow-up visits disrupted. There were no patients who could not receive antiviral treatment, the vaccination rate of the patients was high, and the vaccines were well tolerated.

COVID-19, ¿un conflicto ético? / COVID-19, an ethical conflict?

Exposición sobre posibles dilemas éticos ante la pandemia Covid-19 desde los comité de ética en investigación, en relación a la validación de resultados y distribución de diferentes vacunas, y a los criterios objetivos en la toma de decisiones con respecto a las conductas médicas aprobadas y permitidas durante la pandemia; de modo tal de crear un protocolo especial para la utilización de las futuras generaciones en contextos similares.

Adjuvant-Free COVID-19 Vaccine with Glycoprotein Antigen Oxidized by Periodate Rapidly Elicits Potent Immune Responses.

Modification of antigens to improve their immunogenicity represents a promising direction for the development of protein vaccine. Here, we designed facilely prepared adjuvant-free vaccines in which the N-glycan of SARS-CoV-2 receptor-binding domain (RBD) glycoprotein was oxidized by sodium periodate. This strategy only minimally modifies the glycans and does not interfere with the epitope peptides. The RBD glycoprotein oxidized by high concentrations of periodate (RBDHO) significantly enhanced antigen uptake mediated by scavenger receptors and promoted the activation of antigen-presenting cells. Without any external adjuvant, two doses of RBDHO elicited 324- and 27-fold increases in IgG antibody titers and neutralizing antibody titers, respectively, compared to the unmodified RBD antigen. Meanwhile, the RBDHO vaccine could cross-neutralize all of the SARS-CoV-2 variants of concern. In addition, RBDHO effectively enhanced cellular immune responses. This study provides a new insight for the development of adjuvant-free protein vaccines.

DNA-scaffolded multivalent vaccine against SARS-CoV-2.

Short peptides are poor immunogens. One way to increase their immune responses is by arraying immunogens in multivalency. Simple and efficient scaffolds for spatial controlling the inter-antigen distance and enhancing immune activation are required. Here, we report a molecular vaccine design principle that maximally drives potent SARS-CoV-2 RBD subunit vaccine on DNA duplex to induce robust and efficacious immune responses in vivo. We expect that the DNA-peptide epitope platform represents a facile and generalizable strategy to enhance the immune response. STATEMENT OF SIGNIFICANCE: DNA scaffolds offer a biocompatible and convenient platform for arraying immunogens in multivalency antigenic peptides, and spatially control the inter-antigen distance. This can effectively enhance immune response. Peptide (instead of entire protein) vaccines are highly attractive. However, short peptides are poor immunogens. Our DNA scaffolded multivalent peptide immunogen system induced robust and efficacious immune response in vivo as demonstrated by the antigenic peptide against SARS-CoV-2. The present strategy could be readily generalized and adapted to prepare multivalent vaccines against other viruses or disease. Particularly, the different antigens could be integrated into one single vaccine and lead to super-vaccines that can protect the host from multiple different viruses or multiple variants of the same virus.

The COVID-19 vaccines and menstrual disorders.

OBJECTIVE: The COVID-19 vaccination has been linked to numerous reports of menstrual disorders as potential side effects. However, menstrual cycle results after vaccination were not collected throughout clinical trials. According to other research, COVID-19 vaccination and menstrual disorders have no discernible connection, and menstrual disorders are temporary. SUBJECTS AND METHODS: We asked questions about menstruation disturbances following the first and second doses of the COVID-19 vaccine in a population-based cohort of adult Saudi women to determine whether the vaccination is linked to menstrual cycle irregularities. RESULTS: According to the results, 63.9% of women experienced variations in their menstrual cycle either after the first or second dose. Such results show that COVID-19 vaccination impacts women's menstrual cycles. However, there is no need for concern because the alterations are relatively minor, and the menstrual cycle usually returns to normal within two months. Additionally, there are no obvious distinctions between the various vaccine types or body mass. CONCLUSIONS: Our findings support and explain the self-reports of menstrual cycle variations. We have discussed reasons for these problems that describe the mechanism of the relationship between them and the immune response. Such reasons will help prevent hormonal imbalances and the influence of therapies and immunizations on the reproductive system.

Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA.

The SARS-CoV-2 betacoronavirus pandemic has claimed more than 6.5 million lives and, despite the development and use of COVID-19 vaccines, remains a major global public health problem. The development of specific drugs for the treatment of this disease remains a very urgent task. In the context of a repurposing strategy, we previously screened a library of nucleoside analogs showing different types of biological activity against the SARS-CoV-2 virus. The screening revealed compounds capable of inhibiting the reproduction of SARS-CoV-2 with EC50 values in the range of 20-50 µM. Here we present the design and synthesis of various analogs of the leader compounds, the evaluation of their cytotoxicity and antiviral activity against SARS-CoV-2 in cell cultures, as well as experimental data on RNA-dependent RNA polymerase inhibition. Several compounds have been shown to prevent the interaction between the SARS-CoV-2 RNA-dependent RNA polymerase and the RNA substrate, likely inhibiting virus replication. Three of the synthesized compounds have also been shown to inhibit influenza virus. The structures of these compounds can be used for further optimization in order to develop an antiviral drug.

Self-Adjuvanting Protein Vaccine Conjugated with a Novel Synthetic TLR4 Agonist on Virus-Like Liposome Induces Potent Immunity against SARS-CoV-2.

Exploring potent adjuvants and new vaccine strategies is crucial for the development of protein vaccines. In this work, we synthesized a new TLR4 agonist, structurally simplified lipid A analogue GAP112, as a potent built-in adjuvant to improve the immunogenicity of SARS-CoV-2 spike RBD protein. The new TLR4 agonist GAP112 was site-selectively conjugated on the N-terminus of RBD to construct an adjuvant-protein conjugate vaccine in a liposomal formulation. It is the first time that a TLR4 agonist is site-specifically and quantitatively conjugated to a protein antigen. Compared with an unconjugated mixture of GAP112/RBD, a two-dose immunization of the GAP112-RBD conjugate vaccine strongly activated innate immune cells, elicited a 223-fold increase in RBD-specific antibodies, and markedly enhanced T-cell responses. Antibodies induced by GAP112-RBD also effectively cross-neutralized SARS-CoV-2 variants (Delta/B.1.617.2 and Omicron/B.1.1.529). This conjugate strategy provides an effective method to greatly enhance the immunogenicity of antigen in protein vaccines against SARS-CoV-2 and other diseases.

Microarray Profiling of Vaccination-Induced Antibody Responses to SARS-CoV-2 Variants of Interest and Concern.

Mutations in surface proteins enable emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to escape a substantial fraction of neutralizing antibodies and may thus weaken vaccine-driven immunity. To compare available vaccines and justify revaccination, rapid evaluation of antibody (Ab) responses to currently circulating SARS-CoV-2 variants of interest (VOI) and concern (VOC) is needed. Here, we developed a multiplex protein microarray-based system for rapid profiling of anti-SARS-CoV-2 Ab levels in human sera. The microarray system was validated using sera samples from SARS-CoV-2-free donors and those diagnosed with COVID-19 based on PCR and enzyme immunoassays. Microarray-based profiling of vaccinated donors revealed a substantial difference in anti-VOC Ab levels elicited by the replication-deficient adenovirus vector-base (Sputnik V) and whole-virion (CoviVac Russia COVID-19) vaccines. Whole-virion vaccine-induced Abs showed minor but statistically significant cross-reactivity with the human blood coagulation factor 1 (fibrinogen) and thrombin. However, their effects on blood clotting were negligible, according to thrombin time tests, providing evidence against the concept of pronounced cross-reactivity-related side effects of the vaccine. Importantly, all samples were collected in the pre-Omicron period but showed noticeable responses to the receptor-binding domain (RBD) of the Omicron spike protein. Thus, using the new express Ab-profiling system, we confirmed the inter-variant cross-reactivity of the anti-SARS-CoV-2 Abs and demonstrated the relative potency of the vaccines against new VOCs.

Six-month humoral and cellular immune response to the third dose of BNT162b2 anti-SARS-CoV-2 vaccine in patients with solid tumors: a longitudinal cohort study with a focus on the variants of concern.

BACKGROUND: The role and the durability of the immunogenicity of the third dose of vaccine against COVID-19 variants of concern in cancer patients have to be elucidated. PATIENTS AND METHODS: We have prospectively evaluated the immunogenicity of the third dose of the SARS-CoV-2 BNT162b2 messenger RNA vaccine in triggering both humoral and cell-mediated immune response in patients with solid tumors undergoing active treatment 6 months after the booster. Neutralizing antibody (NT Ab) titers and total anti-spike immunoglobulin G concentrations were measured in serum. Heparinized whole blood samples were used for the SARS-CoV-2 interferon-γ release assay (IGRA). RESULTS: Six months after the third dose only two patients (2.4%) showed negative spike-specific immunoglobulin G antibody levels (<33.8 BAU/ml). The median level of SARS-CoV-2 NT Abs decreased and only 39/83 (47%) subjects showed maximum levels of NT Abs. T-cellular positive response was observed in 38/61 (62.3%) patients; the highest median level of response was observed 21 days after the third dose (354 mIU/ml, interquartile range 83.3-846.3 mIU/ml). The lowest median level of NT Ab response was observed against the Omicron variant (1 : 10, interquartile range 1 : 10-1 : 40) with a significant reduced rate of responder subjects with respect to the wild-type strain (77.5% versus 95%; P = 0.0022) and Delta variant (77.5% versus 93.7%; P = 0.0053). During the follow-up period, seven patients (8%) had a confirmed post-vaccination infection, but none of them required hospitalization or oxygen therapy. CONCLUSIONS: Our work highlights a significant humoral and cellular immune response among patients with solid tumors 6 months after the third BNT162b2 vaccine dose, although a reduction in neutralizing activity against Omicron was observed.

Impaired humoral and cellular response to primary COVID-19 vaccination in patients less than 2 years after allogeneic bone marrow transplant.

Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.

mRNA-1273 and Ad26.COV2.S vaccines protect against the B.1.621 variant of SARS-CoV-2.

BACKGROUND: Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, viral variants with greater transmissibility or immune-evasion properties have arisen, which could jeopardize recently deployed vaccine- and antibody-based countermeasures. METHODS: Here, we evaluated in mice and hamsters the efficacy of a pre-clinical version of the Moderna mRNA vaccine (mRNA-1273) and the Johnson & Johnson recombinant adenoviral-vectored vaccine (Ad26.COV2.S) against the B.1.621 (Mu) variant of SARS-CoV-2, which contains spike mutations T95I, Y144S, Y145N, R346K, E484K, N501Y, D614G, P681H, and D950N. FINDINGS: Immunization of 129S2 and K18-human ACE2 transgenic mice with the mRNA-1273 vaccine protected against weight loss, lung infection, and lung pathology after challenge with the B.1.621 or WA1/2020 N501Y/D614G SARS-CoV-2 strain. Similarly, immunization of 129S2 mice and Syrian hamsters with a high dose of Ad26.COV2.S reduced lung infection after B.1.621 virus challenge. CONCLUSIONS: Thus, immunity induced by the mRNA-1273 or Ad26.COV2.S vaccine can protect against the B.1.621 variant of SARS-CoV-2 in multiple animal models. FUNDING: This study was supported by the NIH (R01 AI157155 and U01 AI151810), NIAID Centers of Excellence for Influenza Research and Response [CEIRR] contracts 75N93021C00014 and 75N93021C00016, and the Collaborative Influenza Vaccine Innovation Centers [CIVIC] contract 75N93019C00051. It was also supported, in part, by the National Institutes of Allergy and Infectious Diseases Center for Research on Influenza Pathogenesis (HHSN272201400008C) and the Japan Program for Infectious Diseases Research and Infrastructure (JP21wm0125002) from the Japan Agency for Medical Research and Development (AMED).

Low-Dose SARS-CoV-2 S-Trimer with an Emulsion Adjuvant Induced Th1-Biased Protective Immunity.

During the sustained COVID-19 pandemic, global mass vaccination to achieve herd immunity can prevent further viral spread and mutation. A protein subunit vaccine that is safe, effective, stable, has few storage restrictions, and involves a liable manufacturing process would be advantageous to distribute around the world. Here, we designed and produced a recombinant spike (S)-Trimer that is maintained in a prefusion state and exhibits a high ACE2 binding affinity. Rodents received different doses of S-Trimer (0.5, 5, or 20 µg) antigen formulated with aluminum hydroxide (Alum) or an emulsion-type adjuvant (SWE), or no adjuvant. After two vaccinations, the antibody response, T-cell responses, and number of follicular helper T-cells (Tfh) or germinal center (GC) B cells were assessed in mice; the protective efficacy was evaluated on a Syrian hamster infection model. The mouse studies demonstrated that adjuvating the S-Trimer with SWE induced a potent humoral immune response and Th1-biased cellular immune responses (in low dose) that were superior to those induced by Alum. In the Syrian hamster studies, when S-Trimer was adjuvanted with SWE, higher levels of neutralizing antibodies were induced against live SARS-CoV-2 from the original lineage and against the emergence of variants (Beta or Delta) with a slightly decreased potency. In addition, the SWE adjuvant demonstrated a dose-sparing effect; thus, a lower dose of S-Trimer as an antigen (0.5 µg) can induce comparable antisera and provide complete protection from viral infection. These data support the utility of SWE as an adjuvant to enhance the immunogenicity of the S-Trimer vaccine, which is feasible for further clinical testing.

Comparison of antibody responses after the 1st and 2nd doses of COVID-19 vaccine with those of patients with mild or severe COVID-19.

BACKGROUND/AIMS: Data comparing the antibody responses of different coronavirus disease 2019 (COVID-19) vaccine platforms according to dose with natural severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection-induced antibody responses are limited. METHODS: Blood samples from adult patients with mild and severe COVID-19 and healthcare workers who received ChAdOx1 nCoV-19 vaccine (2nd dose at 12-week intervals) and BNT162b2 vaccine (2nd dose at 3-week intervals) were collected and compared by immunoglobulin G immune responses to SARS-CoV-2 specific spike protein using an in-house-developed enzyme-linked immunosorbent assay. RESULTS: A total of 53 patients, including 12 and 41 with mild and severe COVID-19, respectively, were analyzed. In addition, a total of 73 healthcare workers, including 37 who received ChAdOx1 nCoV-19 and 36 who received BNT162b2, were enrolled. Antibody responses after the first and second doses of the ChAdOx1 nCoV-19 vaccine or the first dose of the BNT162b2 vaccine were similar to those in convalescent patients with mild COVID-19, but lower than those in convalescent patients with severe COVID-19, respectively. However, after the second dose of the BNT162b2 vaccine, the antibody response was comparable to that in convalescent patients with severe COVID-19. CONCLUSION: Our data suggest that the second dose of mRNA vaccination may be more beneficial in terms of long-term immunity and prevention of SARS-CoV-2 variant infection than a single dose of COVID-19 vaccination or homologous second challenge ChAdOx1 nCoV-19.

Erythro-VLPs: Anchoring SARS-CoV-2 spike proteins in erythrocyte liposomes.

Novel therapeutic strategies are needed to control the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic. Here, we present a protocol to anchor the SARS-CoV-2 spike (S-)protein in the cytoplasmic membranes of erythrocyte liposomes. A surfactant was used to stabilize the S-protein's structure in the aqueous environment before insertion and to facilitate reconstitution of the S-proteins in the erythrocyte membranes. The insertion process was studied using coarse grained Molecular Dynamics (MD) simulations. Liposome formation and S-protein anchoring was studied by dynamic light scattering (DLS), ELV-protein co-sedimentation assays, fluorescent microcopy and cryo-TEM. The Erythro-VLPs (erythrocyte based virus like particles) have a well defined size of ∼200 nm and an average protein density on the outer membrane of up to ∼300 proteins/µm2. The correct insertion and functional conformation of the S-proteins was verified by dose-dependent binding to ACE-2 (angiotensin converting enzyme 2) in biolayer interferometry (BLI) assays. Seroconversion was observed in a pilot mouse trial after 14 days when administered intravenously, based on enzyme-linked immunosorbent assays (ELISA). This red blood cell based platform can open novel possibilities for therapeutics for the coronavirus disease (COVID-19) including variants, and other viruses in the future.

Positive attitudes towards COVID-19 vaccines: A cross-country analysis.

COVID-19 severely impacted world health and, as a consequence of the measures implemented to stop the spread of the virus, also irreversibly damaged the world economy. Research shows that receiving the COVID-19 vaccine is the most successful measure to combat the virus and could also address its indirect consequences. However, vaccine hesitancy is growing worldwide and the WHO names this hesitancy as one of the top ten threats to global health. This study investigates the trend in positive attitudes towards vaccines across ten countries since a positive attitude is important. Furthermore, we investigate those variables related to having a positive attitude, as these factors could potentially increase the uptake of vaccines. We derive our text corpus from vaccine-related tweets, harvested in real-time from Twitter. Using Natural Language Processing (NLP), we derive the sentiment and emotions contained in the tweets to construct daily time-series data. We analyse a panel dataset spanning both the Northern and Southern hemispheres from 1 February 2021 to 31 July 2021. To determine the relationship between several variables and the positive sentiment (attitude) towards vaccines, we run various models, including POLS, Panel Fixed Effects and Instrumental Variables estimations. Our results show that more information about vaccines' safety and the expected side effects are needed to increase positive attitudes towards vaccines. Additionally, government procurement and the vaccine rollout should improve. Accessibility to the vaccine should be a priority, and a collective effort should be made to increase positive messaging about the vaccine, especially on social media. The results of this study contribute to the understanding of the emotional challenges associated with vaccine uptake and inform policymakers, health workers, and stakeholders who communicate to the public during infectious disease outbreaks. Additionally, the global fight against COVID-19 might be lost if the attitude towards vaccines is not improved.