Promising Vaccine Research Articles

Identification of highly conserved surface-exposed peptides of spike protein for multiepitope vaccine design against emerging omicron variants: An immunoinformatic approach

The COVID-19 pandemic, originating in Wuhan in 2019, was caused by SARS-CoV-2, leading to significant global fatalities. Despite the development of vaccines, the virus mutates, creating variants that evade vaccine-induced immunity. To address SARS-CoV-2′s evolving nature, a multiepitope vaccine was developed using immunoinformatics approach, specifically targeting the Omicron variant’s spike protein. This vaccine includes six CD8 + and eleven CD4 + epitopes selected for their immunogenicity, non-toxicity, and significant conservation among former Variants of Concern (VOCs) and Variants of Interest (VOIs), such as Alpha, Beta, Gamma, Delta, Lambda, Mu, R1, and Zeta, as well as current Variants Under Monitoring (VUMs) like XBB.1.5, XBB.1.16, EG.5, BA.2.86, and JN.1. Notably, certain epitopes like ELLHAPATV and PYRVVVLSFELLHAP were fully conserved across all tested variants in the spike protein’s receptor binding domain (RBD). Others, such as NATRFASVYAWNRKR, were fully conserved in all former VOCs and VOIs and 93.33 % in current VUMs, while ERDISTEIYQAGNKP was entirely conserved in current VUMs within the RBD region. The study went on to model, refine, and validate the vaccine prototype’s tertiary structure. Docking experiments and molecular dynamic simulations revealed robust and stable interactions with Toll-like receptor 4. Cloning and codon optimization confirmed successful expression in E. coli. Subsequently, the immunological reaction of the multiepitope vaccine demonstrated that the three-time administration of the prototype significantly enhanced the antibody response while decreasing the number of antigens. The designed vaccine’s epitopes showed significant combined global population coverage of 100 % with 89.75 % for CD8 + and 99.98 % for CD4 + epitopes and conservation across SARS-CoV-2 variants especially in current monitoring omicron subvariants, supporting its broader applicability and potential efficacy. Although, this promising vaccine candidate needs to undergo clinical trials to determine its effectiveness in neutralising SARS-CoV-2.

Unraveling the full impact of SPD_0739: a key effector in S. pneumoniae iron homeostasis.

S. pneumoniae obtains growth essential iron from hemoglobin and other host hemoproteins. Still, the bacterial mechanisms involved are only partially understood, and there are inconsistent reports regarding the function of several transporters implicated in iron uptake. In this study, we clarified the role of PnrA/Spbhp-37, a ligand-binding protein previously linked to nucleoside or heme by different studies. We present data supporting a role in nucleoside scavenging rather than heme import and reveal that PnrA/Spbhp-37 modulates iron and heme uptake, likely by influencing the nucleoside cellular pool. Hence, this work provides a new understanding of a process critical to the pathophysiology of a significant human pathogen. Moreover, PnrA/Spbhp-37 is an abundant and immunogenic surface protein that is highly conserved. Hence, this study also clarifies the function of a promising vaccine target.

Immunoinformatics Design of a Multiepitope Vaccine (MEV) Targeting Streptococcus mutans: A Novel Computational Approach.

Dental caries, a persistent oral health challenge primarily linked to Streptococcus mutans, extends its implications beyond dental decay, affecting over 4 billion individuals globally. Despite its historical association with childhood, dental caries often persists into adulthood with prevalence rates ranging from 60 to 90% in children and 26 to 85% in adults. Currently, there is a dearth of multiepitope vaccines (MEVs) specifically designed to combat S. mutans. To address this gap, we employed an immunoinformatics approach for MEV design, identifying five promising vaccine candidates (PBP2X, PBP2b, MurG, ATP-F, and AGPAT) based on antigenicity and conservation using several tools including CELLO v.2.5, Vaxign, v2.0, ANTIGENpro, and AllerTop v2.0 tools. Subsequent identification of linear B-cell and T-cell epitopes by SVMTrip and NetCTL/NetMHC II tools, respectively, guided the construction of a MEV comprising 10 Cytotoxic T Lymphocyte (CTL) epitopes, 5 Helper T Lymphocyte (HTL) epitopes, and 5 linear B-cell epitopes, interconnected by suitable linkers. The resultant MEV demonstrated high antigenicity, solubility, and structural stability. In silico immune simulations showcased the MEV's potential to elicit robust humoral and cell-mediated immune responses. Molecular docking studies revealed strong interactions between the MEV construct and Toll-Like Receptors (TLRs) and Major Histocompatibility Complex (MHC) molecules. Remarkably, the MEV-TLR-4 complexes exhibited a low energy score, high binding affinity, and a low dissociation constant. The Molecular Dynamic (MD) simulation analysis suggested that MEV-TLR-4 complexes had the highest stability and minimal conformational changes indicating equilibrium within 40 nanosecond time frames. Comprehensive computational analyses strongly support the potential of the proposed MEV to combat dental caries and associated infections. The study's computational assays yielded promising results, but further validation through in vitro and in vivo experiments is needed to assess its efficacy and safety.

A plant-based oligomeric CD2v extracellular domain antigen exhibits equivalent immunogenicity to the live attenuated vaccine ASFV-G-∆I177L.

African swine fever (ASF), caused by the African swine fever virus (ASFV), is a deadly, highly contagious disease in both domestic pigs and wild boar. With mortality up to 100%, the disease has been making a serious impact on the swine industry worldwide. Because no effective antiviral treatment has been observed, proactive prevention such as vaccination remains the key to controlling the outbreak. In the pursuit of expediting vaccine development, our current work has made the first report for heterologous production of the viral outer envelope glycoprotein CD2v extracellular domain (CD2v ED), a proposed promising vaccine antigen candidate in the "green" synthetic host Nicotiana benthamiana. Protein oligomerization strategies were implemented to increase the immunogenicity of the target antigen. Herein, the protein was expressed in oligomeric forms based on the C-terminally fused GCN4pII trimerization motif and GCN4pII_TP oligomerization motif. Quantitative western blot analysis showed significantly higher expression of trimeric CD2v ED_GCN4pII with a yield of about 12mg/100g of fresh weight, in comparison to oligomeric CD2v ED_GCN4pII_TP, revealing the former is the better choice for further studies. The results of purification and size determination by size exclusion chromatography (SEC) illustrated that CD2v ED_GCN4pII was successfully produced in stable oligomeric forms throughout the extraction, purification, and analysis process. Most importantly, purified CD2v ED_GCN4pII was demonstrated to induce both humoral and cellular immunity responses in mice to extents equivalent to those of the live attenuated vaccine ASFV-G-∆I177L, suggesting it as the potential subunit vaccine candidate for preventing ASFV.

Evaluation of a Low-Temperature Immersion Immunization Strategy for the Infectious Spleen and Kidney Necrosis Virus orf037l Gene-Deleted Attenuated Vaccine

Background: Infectious spleen and kidney necrosis virus (ISKNV) poses a significant threat to aquaculture sustainability, particularly affecting mandarin fish (Siniperca chuatsi) and causing significant economic losses. Methods: To address this challenge, this study developed an ISKNV Δorf037l vaccine strain, where the orf037l gene was knocked out. Infection assays conducted at 28 °C showed that the knocking out the orf037l gene decreased the virulence of ISKNV and reduced lethality against mandarin fish by 26.7% compared to wild-type ISKNV. To further diminish residual virulence, the effect of low-temperature (22 °C) immersion immunization was evaluated. Results: The results indicate that low temperature significantly diminished the virulence of the Δorf037l vaccine strain, elevating the survival rate of mandarin fish to 90%. Furthermore, the vaccine strain effectively triggered the expression of crucial immune-related genes, such as IFN-h, IL-1, IκB, Mx, TNF-α, and Viperin, while inducing the production of specific neutralizing antibodies. Low-temperature immersion with Δorf037l achieved a high relative percentage of survival of 92.6% (n = 30) in mandarin fish, suggesting the potential of Δorf037l as a promising immersion vaccine candidate. Conclusions: These findings contribute to advancing fish immersion vaccine development and demonstrate the importance and broad applicability of temperature optimization strategies in vaccine development. Our work carries profound implications for both the theoretical understanding and practical application in aquaculture disease control.

A Head-to-Head Comparative Study of the Replication-Competent Vaccinia Virus and AAV1-Based Malaria Vaccine versus RTS,S/AS01 in Murine Models.

Background/Objectives: We developed a multistage Plasmodium falciparum vaccine using a heterologous prime-boost immunization strategy. This involved priming with a highly attenuated, replication-competent vaccinia virus strain LC16m8Δ (m8Δ) and boosting with adeno-associated virus type 1 (AAV1). This approach demonstrated 100% efficacy in both protection and transmission-blocking in a murine model. In this study, we compared our LC16m8∆/AAV1 vaccine, which harbors a gene encoding Pfs25-PfCSP fusion protein, to RTS,S/AS01 (RTS,S) in terms of immune responses, protective efficacy, and transmission-blocking activity (TBA) in murine models. Methods: Mice were immunized following prime-boost vaccine regimens m8∆/AAV1 or RTS,S and challenged with transgenic Plasmodium berghei parasites. Immune responses were assessed via ELISA, and TB efficacy was evaluated using direct feeding assays. Results: m8∆/AAV1 provided complete protection (100%) in BALB/c mice and moderate (40%) protection in C57BL/6 mice, similar to RTS,S. Unlike RTS,S's narrow focus (repeat region), m8∆/AAV1 triggered antibodies for all PfCSP regions (N-terminus, repeat, and C-terminus) with balanced Th1/Th2 ratios. Regarding transmission blockade, serum from m8∆/AAV1-vaccinated BALB/c mice achieved substantial transmission-reducing activity (TRA = 83.02%) and TB activity (TBA = 38.98%)-attributes not observed with RTS,S. Furthermore, m8∆/AAV1 demonstrated durable TB efficacy (94.31% TRA and 63.79% TBA) 100 days post-immunization. Conclusions: These results highlight m8∆/AAV1's dual action in preventing sporozoite invasion and onward transmission, a significant advantage over RTS,S. Consequently, m8∆/AAV1 represents an alternative and a promising vaccine candidate that can enhance malaria control and elimination strategies.

A compact stem-loop DNA aptamer targets a uracil-binding pocket in the SARS-CoV-2 nucleocapsid RNA-binding domain.

SARS-CoV-2 nucleocapsid (N) protein is a structural component of the virus with essential roles in the replication and packaging of the viral RNA genome. The N protein is also an important target of COVID-19 antigen tests and a promising vaccine candidate along with the spike protein. Here, we report a compact stem-loop DNA aptamer that binds tightly to the N-terminal RNA-binding domain of SARS-CoV-2 N protein. Crystallographic analysis shows that a hexanucleotide DNA motif (5'-TCGGAT-3') of the aptamer fits into a positively charged concave surface of N-NTD and engages essential RNA-binding residues including Tyr109, which mediates a sequence-specific interaction in a uracil-binding pocket. Avid binding of the DNA aptamer allows isolation and sensitive detection of full-length N protein from crude cell lysates, demonstrating its selectivity and utility in biochemical applications. We further designed a chemically modified DNA aptamer and used it as a probe to examine the interaction of N-NTD with various RNA motifs, which revealed a strong preference for uridine-rich sequences. Our studies provide a high-affinity chemical probe for the SARS-CoV-2 N protein RNA-binding domain, which may be useful for diagnostic applications and investigating novel antiviral agents.

Construction and Immunogenicity of a Recombinant Porcine Pseudorabies Virus (PRV) Expressing the Major Neutralizing Epitope Regions of S1 Protein of Variant PEDV

Porcine epidemic diarrhea virus (PEDV) infection causes severe diarrhea and high mortality in neonatal piglets. Pseudorabies causes acute and often fatal infections in young piglets, respiratory disorders in growing pigs, and reproductive failure in sows. In late 2011, pseudorabies virus (PRV) variants occurred in Bartha-K61-vaccine-immunized swine herds, resulting in economic losses to the global pig industry. Therefore, it is essential to develop a safe and effective vaccine against both PEDV and PRV infections. In this study, we constructed a recombinant virus rPRV-PEDV S1 expressing the major neutralizing epitope region (COE, SS2, and SS6) of the PEDV S1 protein by homologous recombination technology and CRISPR/Cas9 gene editing technology, and then evaluated its biological characteristics in vitro and immunogenicity in pigs. The recombinant virus rPRV-PEDV S1 had similar growth kinetics in vitro to the parental rPRV NY-gE−/gI−/TK− strain, and was proven genetically stable in swine testicle (ST) cells and safe for piglets. PEDV S1-specific antibodies were detected in piglets immunized with rPRV-PEDV S1 on the 7th day post-immunization (dpi), and the antibody level increased rapidly at 14–21 dpi. Moreover, the immunized piglets receiving the recombinant virus exhibited alleviated clinical signs and reduced viral load compared to the unvaccinated group following a virulent PEDV HN2021 strain challenge. Also, piglets immunized with rPRV-PEDV S1 developed a PRV-specific humoral immune response and elicited complete protection against a lethal PRV NY challenge. These data indicate that the recombinant rPRV-PEDV S1 is a promising vaccine candidate strain for the prevention and control of PEDV and PRV infections.

Purified Astragalus Polysaccharide Combined with Inactivated Vaccine Markedly Prevents Infectious Haematopoietic Necrosis Virus Infection in Rainbow Trout (Oncorhynchus mykiss).

Rainbow trout (Oncorhynchus mykiss) is experiencing a catastrophic pandemic. In recent years, infectious hematopoietic necrosis virus (IHNV) has spread nationwide, resulting in significant mortality. Currently, there are no available treatments or vaccines for IHNV in China. Here, the Astragalus extract was purified and characterized. Then, we developed an inactivated IHNV vaccine with purified Astragalus polysaccharide (P-APS) as an adjuvant. Safety assays showed that IHNV was successfully inactivated. After a serious IHNV challenge, the cumulative mortality rates were 76.0, 38.0, and 22.1% in control, vaccine, and P-APS + vaccine groups, respectively. P-APS + vaccine was effective at reducing head kidney damage and apoptosis after IHNV challenge by histopathological and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses. The P-APS + vaccine group showed better results in enhancing specific antibodies (IgM) and immune enzyme activities (C3, LZM, GOT, and GPT). RNA-seq revealed that many immune-related pathways were significantly enriched. TLR2, TLR7, C3, IFN-γ, IgM, MHC1, MHC2, MX1, and VIG1 were identified as core genes based on RNA-seq and PPI networks. Mechanistic investigations showed that P-APS + vaccine activates the immune pathway by upregulating the expression of these genes. P-ASP+vaccine induced effective innate and adaptive immune responses that were stronger than single vaccines after vaccination and IHNV challenged. Our findings will provide a promising vaccine candidate against IHNV.

Evaluation of a DNA vaccine with self-designed CpG sequences against J genotype IHNV infection in rainbow trout (Oncorhynchus mykiss)

Rainbow trout suffer from infectious hematopoietic necrosis virus (IHNV) outbreaks, which lead to massive mortality and huge economic loss worldwide. The approved commercial vaccine is used for the prevention of IHN in Canada. Given that Chinese domestic J-genotype isolates are different from North American IHNV isolates, the development of an effective DNA vaccine against Chinese J-genotype isolates is urgent. In this study, we developed a DNA vaccine encoding glycoprotein based on our previously isolated IHNV GS21 strain and self-designed CpG sequences were supplemented as molecular adjuvants. The vaccinated rainbow trout were significantly protected against IHNV with approximately a relative percent survival (RPS) of 94.74 % compared to the unvaccinated group. Moreover, the specific antibody of IgM and neutralizing antibody (NAb) was significantly provoked after the vaccination. Particularly, the antiviral immune response was rapidly evoked in the early stage of vaccination including the up-regulation of Mx-1, IFN-Ⅰ, and IFN-γ. The IHNV load in vaccinated fish was apparently lower than that in the unvaccinated group. Furthermore, the integration of exogenous genes into the host chromosome and the spread of antimicrobial-resistant genes were not found. These results suggested that our vaccine enhances robust immune responses and evokes considerable protection against IHNV with limited genetically modified risk, which is an effective and promising vaccine candidate for further prevention of IHNV outbreaks.

Prophylaxis of respiratory syncytial virus infection: current status and prospects for vaccine development

INTRODUCTION. Respiratory syncytial virus (RSV) is one of the most widespread pathogens that typically cause acute upper and lower respiratory tract infections in children and adults. Monoclonal antibody products have long been used for passive immunoprophylaxis in premature infants with bronchopulmonary dysplasia. However, vaccines have recently been licensed for the prophylactic immunisation of older adults with various risk factors for severe RSV infection (primarily, chronic cardiovascular and respiratory diseases and diabetes mellitus).AIM. This study aimed to review the current status of the development of vaccines for active immunisation against RSV infection, including the epidemiological rationale for their development, clinical trial results for licensed vaccines, recommendations for vaccination, and promising pipeline vaccines for RSV prevention.DISCUSSION. Initially hindered by the unique immunopathogenesis of RSV infection and the genetic hypervariability of RSV for a long time, attempts to develop an RSV vaccine succeeded when international researchers managed to identify a conservative neutralising antibody target capable of inducing specific immunity against RSV. This target, the RSV capsid protein stabilised in its prefusion (pre-F) conformation, can mediate viral entry into the cell following a conformational change. Several subunit vaccines based on recombinant pre-F proteins have successfully passed clinical trials and have been approved for the immunisation of older adults. In addition, one of these vaccines has been recommended for use during pregnancy to prevent RSV infection in newborns and infants. Currently, programmes are being implemented to develop novel RSV vaccines based on messenger RNA (mRNA) and non-replicating attenuated influenza vectors. This article examines and summarises the efficacy and safety parameters of two RSV vaccines approved in multiple countries around the world. Both vaccines have satisfactory safety profiles and comparable prophylactic efficacy parameters.CONCLUSIONS. Prelicensure clinical trials of novel RSV vaccines, including those being developed in the Russian Federation, should include prophylactic efficacy assessments in target patient populations. For vaccines approved by leading international regulators, clinical trials required for approval in the Russian Federation will be limited to bridging studies confirming the immunogenicity and safety of the vaccines.

Immunoprotective effect of recombinant Lactobacillus plantarum expressing largemouth bass virus MCP on largemouth bass

Largemouth bass virus (LMBV) is an infectious pathogen that causes high mortality rates in largemouth bass, and outbreaks of this virus can significantly harm the aquaculture industry. Currently, no vaccine has been developed that can effectively prevent the transmission of LMBV. In this study, we constructed a recombinant Lactobacillus plantarum (L. plantarum) strain capable of expressing the MCP gene of LMBV and displaying this protein on its surface; then, we evaluated the immunoprotective effect of this recombinant bacterium on largemouth bass. Western blotting, immunofluorescence, and flow cytometry confirmed that MCP was successfully expressed and anchored on the surfaces of NC8 cells. Immunization of largemouth bass with NC8-pSIP409-pgsA'-MCP via the oral feeding route induced CD4, CD8, IL-1β, and IL-6 gene expression. In addition, NC8-pSIP409-pgsA'-MCP at different CFUs increased the survival of largemouth bass after LMBV infection; in particular, NC8-pSIP409-pgsA'-MCP (109 CFU) resulted in approximately 30% survival. NC8-pSIP409-pgsA'-MCP immunization alleviated the pathological changes in the liver and spleen, exerting a more advantageous protective effect. These data suggest that the recombinant L. plantarum strain NC8-pSIP409-pgsA'-MCP can increase the resistance of largemouth bass to LMBV infection and that this strain is a promising candidate oral vaccine for the prevention of LMBV infection.

Cistanche deserticola polysaccharide-functionalized dendritic fibrous nano-silica as oral delivery system for H9N2 vaccine to promote systemic and mucosal immune response.

Most infectious diseases are caused by pathogens that invade the body tissues through mucosal tract. Therefore, it is essential to develop effective vaccines administered through the mucosa as a first-line of defense against major infectious diseases. Oral delivery of vaccines is currently of great interest due to its potential to elicit both mucosal and systemic immune responses, high compliance rate and non-invasive nature. However, their development is limited by the challenging gastrointestinal (GI) environment, the low permeability of the mucus barrier, and the lack of effective and safe mucosal adjuvants. Currently, nanoparticle-based strategies show significant potential for improving oral vaccine delivery systems. Herein, the dendritic fibrous nano-silica (DFNS) grafted with Cistanche deserticola polysaccharide (CDP) nanoparticles (CDP-DFNS) were developed for oral delivery of H9N2 antigen. CDP-DFNS induced the activation of macrophages, thereby enhancing antigen uptake in vitro. Additionally, CDP-DFNS/H9N2 significantly activated the dendritic cells (DCs) in Peyer's patches (PPs), and T/B cells in mesenteric lymph nodes (MLNs). Moreover, CDP-DFNS/H9N2 enhanced the HI titers and levels of H9N2-specific antibody IgG, secretory IgA (SIgA) and H9N2-specific IgA in intestinal and respiratory mucosa, as well as Th-associated cytokines. Our results indicate that CDP-DFNS could be a promising oral vaccine adjuvant delivery system.

The dengue vaccine: a major scientific challenge and a public health issue

Almost half of the world's population is exposed to the risk of transmission of the four dengue virus serotypes (DENV 1-4), by mosquitoes of the genus Aedes. A dengue vaccine is effective if it induces prolonged protective immunity against all circulating viral strains, irrespective of the age and infection history of the vaccinated subject. An effective vaccine strategy against dengue is based on the injection of live attenuated viruses in a tetravalent formulation. In this review, we present the most promising candidate vaccines against dengue, their successes and also the questions raised by the correlates of protection that have been adopted to assess their level of effectiveness against the disease.

Mtb-Specific HLA-E-Restricted T Cells Are Induced during Mtb Infection but Not after BCG Administration in Non-Human Primates and Humans.

Background: Novel vaccines targeting the world's deadliest pathogen Mycobacterium tuberculosis (Mtb) are urgently needed as the efficacy of the Bacillus Calmette-Guérin (BCG) vaccine in its current use is limited. HLA-E is a virtually monomorphic unconventional antigen presentation molecule, and HLA-E-restricted Mtb-specific CD8+ T cells can control intracellular Mtb growth, making HLA-E a promising vaccine target for Mtb. Methods: In this study, we evaluated the frequency and phenotype of HLA-E-restricted Mtb-specific CD4+/CD8+ T cells in the circulation and bronchoalveolar lavage fluid of two independent non-human primate (NHP) studies and from humans receiving BCG either intradermally or mucosally. Results: BCG vaccination followed by Mtb challenge in NHPs did not affect the frequency of circulating and local HLA-E-Mtb CD4+ and CD8+ T cells, and we saw the same in humans receiving BCG. HLA-E-Mtb T cell frequencies were significantly increased after Mtb challenge in unvaccinated NHPs, which was correlated with higher TB pathology. Conclusions: Together, HLA-E-Mtb-restricted T cells are minimally induced by BCG in humans and rhesus macaques (RMs) but can be elicited after Mtb infection in unvaccinated RMs. These results give new insights into targeting HLA-E as a potential immune mechanism against TB.

Production of Norovirus VLPs of the Nine Representative Genotypes Widely Distributed in Japan using the Silkworm-Baculovirus Expression Vector System

Norovirus (NoV) is one of the major causes of acute viral gastroenteritis in humans. Genetic variation is abundant, and prevalent genotypes vary from year to year and region to region. Since NoVs are difficult to amplify in cultured cells, genome RNA-free virus-like particles (VLPs) that mimic the capsid structure of the virus are promising vaccine candidates for the prevention of NoVs infection, and the development of multivalent VLP vaccines is required to prevent NoV infection in a wide range of genotypes. In this study, we attempted to produce NoV VLPs of the top nine genotypes that have a history of epidemics in Japan using the silkworm-baculovirus expression vector system (silkworm-BEVS), which has a proven track record in the mass production of recombinant proteins. In silkworm pupae infected with recombinant baculoviruses constructed to express VP1s, the major protein that forms VLP, the NoV VP1 protein was expressed in large amounts. Most genotypes of VP1 accumulated in the cytoplasm as soluble proteins, but solubility was reduced for that of two genotypes. VP1s of five genotypes could be purified in large quantities (>0.9mg per pupa) by a two-step purification process, and gel filtration chromatography analysis confirmed the formation of VLPs. This study demonstrates the utility of silkworm-BEVS in producing NoV VLPs of multiple genotypes and provides the basis for the development of a multivalent vaccine against genetically diverse NoV infections.

Effects of age and gender on immunogenicity and reactogenicity of SpikoGen recombinant spike protein vaccine: a post-hoc analysis

SpikoGen® COVID-19 vaccine is based on the spike protein extracellular domain of the ancestral Wuhan-Hu-1 strain modified by removal of the furin cleavage site and addition of stabilising mutations expressed as a recombinant protein in insect cells. It is formulated with Advax-CpG55.2™ adjuvant to ensure optimal immunogenicity. In this study, data from several SpikoGen® clinical trials was retrospectively analysed to assess for any effect of gender or age on seroconversion, neutralizing antibody levels or the incidence of adverse events. Following the 1st dose, older age was associated with a reduced rate of fatigue (RR 0.97, p < 0.001), headache (RR 0.98, p = 0.034) and myalgia (RR 0.97, p=0.016), following the 2nd dose, the rate of fatigue (RR 0.98, p = 0.017) but following the 3rd dose no effect of age on adverse events was evident. Similarly, following the 1st dose, men reported a 19% lower incidence of fatigue, 36% lower incidence of headache and 28% lower incidence of myalgia when compared to women. Interestingly, there was no relationship between age or gender and serum neutralizing antibody levels, although after each vaccine dose there was a consistent trend to women having a higher seroconversion rate. There was no correlation between neutralizing antibody levels and adverse events. Unlike what is seen with mRNA vaccines, reactogenicity trended lower after each subsequent SpikoGen® dose. Overall, SpikoGen® exhibited positive immunogenicity and low reactogenicity, indicating that a low incidence of adverse events does not equate to poor immunogenicity. SpikoGen® remains a promising protein-based vaccine platform for COVID-19 protection.

Genetic polymorphism of Duffy binding protein in Pakistan Plasmodium vivax isolates

Plasmodium vivax Duffy binding protein (PvDBP) is crucial for erythrocyte invasion, interacting with the Duffy Antigen Receptor for Chemokines (DARC) on the erythrocyte surface. The amino-terminal cysteine-rich region II of PvDBP (PvDBPII) is a promising blood stage vaccine candidate, yet the genetic polymorphisms of this protein in global P. vivax isolates complicate the design of effective vaccines against vivax malaria. This study analyzed the genetic polymorphism of PvDBPII in Pakistan P. vivax isolates. A total of 29 single nucleotide polymorphisms (SNPs), including 22 nonsynonymous SNPs, were identified in 118 Pakistan PvDBPII. Most amino acid substitutions occurred in subdomains II and III, with six commonly observed in the global PvDBPII population. The amino acid change patterns in Pakistan PvDBPII generally mirrored those in global PvDBPII, although the frequencies of amino acid changes varied by country. Nucleotide diversity in Pakistan PvDBPII was comparable to that found in global PvDBPII. Evidence of natural selection and recombination in Pakistan PvDBPII aligned with observations in global PvDBPII. Analysis of the haplotype network of global PvDBPII revealed a complexed network of 167 haplotypes, but no geographical clustering was observed. The findings are crucial for understanding the genetic characteristics of Pakistan PvDBPII. A comprehensive analysis of nucleotide diversity and evolutionary trends in the global PvDBPII population offers valuable insights for the development of vivax malaria vaccines based on this antigen.

Pre-challenge gut microbial signature predicts RhCMV/SIV vaccine efficacy in rhesus macaques.

Rhesus cytomegalovirus expressing simian immunodeficiency virus (RhCMV/SIV) vaccines protect ~59% of vaccinated rhesus macaques against repeated limiting-dose intra-rectal exposure with highly pathogenic SIVmac239M, but the exact mechanism responsible for the vaccine efficacy is unknown. It is becoming evident that complex interactions exist between gut microbiota and the host immune system. Here, we aimed to investigate if the rhesus gut microbiome impacts RhCMV/SIV vaccine-induced protection. Three groups of 15 rhesus macaques naturally pre-exposed to RhCMV were vaccinated with RhCMV/SIV vaccines. Rectal swabs were collected longitudinally both before SIV challenge (after vaccination) and post-challenge and were profiled using 16S rRNA based microbiome analysis. We identified ~2,400 16S rRNA amplicon sequence variants (ASVs), representing potential bacterial species/strains. Global gut microbial profiles were strongly associated with each of the three vaccination groups, and all animals tended to maintain consistent profiles throughout the pre-challenge phase. Despite vaccination group differences, by using newly developed compositional data analysis techniques, we identified a common gut microbial signature predictive of vaccine protection outcome across the three vaccination groups. Part of this microbial signature persisted even after SIV challenge. We also observed a strong correlation between this microbial signature and an early signature derived from whole blood transcriptomes in the same animals. Our findings indicate that changes in gut microbiomes are associated with RhCMV/SIV vaccine-induced protection and early host response to vaccination in rhesus macaques.IMPORTANCEThe human immunodeficiency virus (HIV) has infected millions of people worldwide. Unfortunately, still there is no vaccine that can prevent or treat HIV infection. A promising pre-clinical HIV vaccine based on rhesus cytomegalovirus (RhCMV) expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) provides sustained, durable protection against SIV challenge in ~59% of vaccinated rhesus macaques. There is an urgent need to understand the cause of this protection vs non-protection outcome. In this study, we profiled the gut microbiomes of 45 RhCMV/SIV vaccinated rhesus macaques and identified gut microbial signatures that were predictive of RhCMV/SIV vaccination groups and vaccine protection outcomes. These vaccine protection-associated microbial features were significantly correlated with early vaccine-induced host immune signatures in whole blood from the same animals. These findings show that the gut microbiome may be involved in RhCMV/SIV vaccine-induced protection, warranting further research into the impact of the gut microbiome in human vaccine trials.

Immune Responses to Methicillin-Resistant Staphylococcus aureus Infections and Advances in the Development of Vaccines and Immunotherapies.

Staphylococcus aureus (SA) is a major bacterial pathogen and causes a wide range of clinical infections in humans leading to severe outcomes including meningitis, endocarditis, and sepsis. This literature review examines studies on host immune responses after infections with SA and methicillin-resistant Staphylococcus aureus (MRSA) and their immune evasion mechanisms. Furthermore, information about vaccines and immunotherapies against SA and MRSA is reviewed. We found promising toxoid vaccine approaches, which deserve further research. We also found support for antitoxin therapies and immunomodulating therapies as high-potential research areas. Although many promising vaccines and immunotherapy candidates have been studied in animal models, more human clinical studies are needed to confirm their long-term safety and efficacy.