Search Results (74)

Background: Since the introduction of Pasteur’s rabies vaccine in 1885, rabies prophylaxis and post-exposure prophylaxis (PEP) have been widely administered globally under the recommendation of the World Health Organization (WHO). However, 124 documented cases of PEP failure had been reported worldwide between 1980 and 2023. Additionally, sporadic media reports from China showed occasional PEP failures between 2017 and 2024. Rabies remains a serious public health problem in over 150 countries and regions. Methods: In this review, we summarize PEP procedures recommended by the Advisory Committee on Immunization Practices (ACIP) and the WHO. We also analyze potential contributing factors to PEP failure, propose a concept of circulating antibodies, and discuss their roles in PEP. Furthermore, we summarize key guidelines for clinical trial design from the U.S. Food and Drug Administration (FDA) and China’s Center for Drug Evaluation (CDE), as well as the latest developments in monoclonal antibody (cocktail) therapies. Results: Adherence to core PEP practices, such as wound cleansing, infiltration of wounds with immunoglobulin (mAbs), and administration of vaccines, and broader societal involvement are crucial for preventing rabies infection in most cases. For high-risk exposures or immunocompromised individuals, the provision of circulating antibodies through high-dose human rabies immune globulin (HRIG) or mAbs is of utmost importance for preventing PEP failure. Conclusions: Early, high-concentration circulating antibodies are important for preventing PEP failure. Addressing the global issue of rabies requires involvement of the entire society. Only through collective efforts can we tackle this neglected disease and achieve WHO’s goal of “zero by 30”. Full article

Toxoplasma gondii, a parasitic protozoan, causes zoonotic infections with severe health impacts in humans and warm-blooded animals, underscoring the urgent need for effective vaccines to control these infections. In this study, a DNA vaccine encoding TgROP5, TgROP18, TgGRA7, TgGRA15, and TgMIC6 was formulated using the eukaryotic expression vector pVAX I. IL-24 was delivered as a molecular adjuvant using plasmid pVAX-IL-24. BALB/c, C57BL/6, and Kunming mouse strains received the DNA immunization, after which antibody levels, cytokine production, and lymphocyte surface markers were analyzed to assess immune responses. Additionally, survival rates and brain cyst counts were measured 1 to 2 months post-vaccination in experimental models of toxoplasmosis. As a result, compared to controls, the DNA vaccine cocktail significantly increased serum IgG levels, Th1 cytokine production, and proportions of CD4+/CD8+ T cells, leading to extended survival and reduced brain cyst counts post-challenge with T. gondii ME49. Furthermore, the five-gene DNA vaccine cocktail conferred greater protection compared to single-gene immunizations. Co-administration of IL-24 significantly enhanced the immune efficacy of the multi-gene DNA vaccination. Our findings suggest that IL-24 is an effective molecular adjuvant, enhancing the protective immunity of DNA vaccines against T. gondii, supporting its potential role in vaccine strategies targeting other apicomplexan parasites. Full article

Background/Objectives: Chronic illness after COVID-19 vaccination (longvax) lacks a therapeutic protocol anchored in pathophysiology. Persistent vaccine derived spike protein appears to trigger microvascular fibrin amyloid microclots, immune dysfunction, pathogen reactivation and multisystem injury. This article proposes an integrative approach, Vaxtherapy, to tackle these mechanisms. Methods: A narrative synthesis of peer reviewed literature from 2021 to 2025 on spike related injury and vaccine adverse events was conducted, supplemented by clinical case series and mechanistic observations from long COVID. The findings were arranged into a four stage therapeutic sequence ordered by pathophysiological precedence. Results: Stage one aims to reopen hypoperfused tissue through oral fibrinolytics that degrade fibrin amyloid resistant microclots; stage two intends to neutralise circulating or tissue bound spike via a receptor binding domain monoclonal antibody cocktail; stage three seeks to eliminate reactivated viral or microbial reservoirs with targeted antivirals or antimicrobials once perfusion is improved; and stage four aspires to support tissue repair with mitochondrial supplements and, when indicated, cell based therapies. Omitting or reordering stages may reduce efficacy or foster resistance. Conclusions: This hypothesis driven framework outlines a biologically plausible roadmap for longvax research. By matching interventions to specific mechanisms (fibrinolysis, spike neutralisation, pathogen clearance and regeneration), it aims to guide controlled trials and compassionate pilot programs directed at durable recovery rather than chronic symptom management. Full article

Background/Objectives: Identification and characterization of broadly neutralizing monoclonal antibodies from individuals exposed to SARS-CoV-2, either by infection or vaccination, can inform the development of next-generation vaccines and antibody therapeutics with pan-SARS-CoV-2 protection. Methods: Through single B cell sorting and RT-PCR, monoclonal antibodies (mAbs) were isolated from a donor who experienced a BA.5 or BF.7 breakthrough infection after three doses of inactivated vaccines. Their binding and neutralizing capacities were measured with ELISA and a pseudovirus-based neutralization assay, respectively. Their epitopes were mapped by competition ELISA and site-directed mutation. Results: Among a total of 67 spike-specific mAbs cloned from the donor, four mAbs (KXD643, KXD652, KXD681, and KXD686) can neutralize all tested SARS-CoV-2 variants from wild-type to KP.3. Moreover, KXD643, KXD652, and KXD681 belong to a clonotype encoded by IGHV5-51 and IGKV1-13 and recognize the cryptic and conserved RBD-8 epitope on the receptor-binding domain (RBD). In contrast, KXD686 is encoded by IGHV1-69 and IGKV3-20 and targets a conserved epitope (NTD Site iv) outside the antigenic supersite (NTD Site i) of the N-terminal domain (NTD). Notably, antibody cocktails containing these two groups of mAbs can neutralize SARS-CoV-2 more potently due to synergistic effects. In addition, bispecific antibodies derived from KXD643 and KXD686 demonstrate further improved neutralizing potency compared to antibody cocktails. Conclusions: These four mAbs can be developed as candidates of pan-SARS-CoV-2 antibody therapeutics through further antibody engineering. On the other hand, vaccines designed to simultaneously elicit neutralizing antibodies towards RBD-8 and NTD Site iv have the potential to provide pan-SARS-CoV-2 protection. Full article

Background. The pathogenic coronaviruses (CoVs) MERS-CoV and SARS-CoV-2, which are responsible for the MERS outbreak and the COVID-19 pandemic, respectively, continue to infect humans, with significant adverse outcomes. There is a continuing need to develop mucosal vaccines against these respiratory viral pathogens to prevent entry and replication at mucosal sites. The receptor-binding domain (RBD) of the CoV spike (S) protein is a critical vaccine target, and glycan masking is a unique approach for designing subunit vaccines with improved neutralizing activity. Methods. We evaluated the efficacy of mucosal immunity, broad neutralizing activity, and cross-protection afforded by a combined glycosylated mucosal subunit vaccine encoding the RBDs of the original SARS-CoV-2 strain (SARS2-WT-RBD), the Omicron-XBB.1.5 variant (SARS2-Omi-RBD), and MERS-CoV (MERS-RBD). Results. Intranasal administration of the three-RBD protein cocktail induced effective, durable IgA and systemic IgG antibodies specific for the S protein of these CoVs, thereby neutralizing infection by pseudotyped SARS-CoV-2-WT, Omicron-XBB.1.5, and MERS-CoV. The mucosal vaccine cocktail protected immunized mice from challenge with SARS-CoV-2 Omicron-XBB.1.5 and MERS-CoV, leading to a significant reduction in the viral titers in the lungs. By contrast, the individual glycosylated RBD proteins only induced such immune responses and neutralizing antibodies against either SARS-CoV-2 or MERS-CoV, protecting against subsequent challenge with either SARS-CoV-2 or MERS-CoV; they did not provide simultaneous protection against both CoVs. Conclusions. This study describes a unique strategy for designing efficacious mucosal subunit vaccines that induce durable mucosal immunity, cross-neutralizing activity, and cross-protection against SARS-CoV-2 and MERS-CoV, highlighting the potential for the design of mucosal vaccines against other pathogens. Full article

Background: Endemic viruses are becoming increasingly the norm, and the development of a rapid and effective vaccine is necessary. Methods: Here, we used our StealthX^TM exosome platform to express either Influenza H3 (StealthX^TM-Hemagglutinin, STX-H3), SARS-CoV-2 Delta spike (StealthX^TM-Spike, STX-S) or respiratory syncytial virus proteins (StealthX^TM-RSV fusion protein, STX-RSV) protein on the membrane surface and facilitate their trafficking to the exosomes. Results: The administration of exosomes carrying one of the antigens by themselves resulted in a strong immune response with the production of a potent humoral and cellular immune response in mice. Interestingly, these effects were obtained with the administration of nanograms of protein and without adjuvant. We tested the possibility of manufacturing a multivalent vaccine by combining exosomes expressing either STX-H3, STX-RSV or STX-S exosomes in the same formulation, in a “mix and match” approach. Mice immunized with the cocktail vaccine showed an increased immune response against all three antigens received. Conclusions: The results further demonstrated that our STX trivalent cocktail vaccine elicited a strong immune response, and the magnitude of the responses was comparable to the single antigen administered individually. Our data show that our exosome platform has enormous potential to revolutionize vaccinology by rapidly facilitating antigen presentation, to tackle the fast-evolving viral infections. Full article

African swine fever (ASF), caused by African swine fever virus (ASFV), poses a great threat to the global pig industry. There is an urgent demand for effective and safe vaccines to address this threat. This study reports the generation and evaluation of a recombinant Lactococcus lactis pool, each strain expressing one of eight ASFV antigens (F317L, H171R, D117L, E120R, B602L, CD2v, p54, and p72). We evaluated the immune responses in mice through oral gavage and intramuscular immunization to the recombinant L. lactis pool. The results show that the mice immunized via intramuscular injection induced high-level serum IgG antibodies within 7 d post-primary immunization, which was maintained over an extended period. Additionally, there was a marked increase in the interferon gamma (IFN-γ) and interleukin 10 (IL-10) levels in the sera. In contrast, the mice immunized via oral gavage did not induce obvious serum IgG antibodies. However, they experienced a transient peak of secretory IgA (sIgA) antibodies in fecal samples within 7 d post-primary immunization, which subsequently decreased to levels that were statistically similar to those in the control group. In addition, this study also found that the multi-antigen cocktail vaccination was safe for mice. This study provides a reference for the development and immunization of ASF vaccines with L. lactis as live carriers. Full article

Background: Elite-neutralizer-derived HIV-1 envelopes (Envs), which induce broadly neutralizing antibodies (bnAbs), can inform HIV-1 vaccine design by serving as templates for bnAb-eliciting vaccines. Since single Env-based immunizations are insufficient to induce bnAb responses, sequential regimens using multivalent immunogens or Env cocktails hold greater promise. This underscores the need to develop stable Env trimers from diverse HIV-1 strains, particularly clade-C, which accounts for 50% of global infections and over 90% in India and South Africa. While various platforms exist to stabilize soluble Env trimers for use as antigenic baits and vaccines, stabilizing clade C trimers remains challenging. Methods: We stabilized an HIV-1 clade C trimer based on an Env isolated from a pediatric elite neutralizer (AIIMS_329) using multiple platforms, including SOSIP.v8.2, ferritin nanoparticles (NPs) and I53-50 two-component NPs, followed by characterization of their biophysical, antigenic, and immunogenic properties. Results: The stabilized 329 Envs showed binding to multiple HIV-1 bnAbs, with negligible binding to non-neutralizing antibodies. Negative-stain electron microscopy confirmed the native-like conformation of the Envs. Multimerization of 329 SOSIP.v8.2 on ferritin and two-component I53-50 NPs improved the affinity to HIV-1 bnAbs and showed higher immunogenicity in rabbits. Conclusions: The soluble 329 Env protein could serve as an antigenic bait, and multimeric 329 NP Envs are potential vaccine candidates. Full article

Inappropriate and excessive use of antibiotics is responsible for the rapid development of antimicrobial resistance, which is associated with increased patient morbidity and mortality. There is an urgent need to explore new antibiotics or alternative antimicrobial agents. S. aureus a commensal microorganism but is also responsible for numerous infections. In addition to innate resistance to β-lactam antibiotics, S. aureus strains resistant to methicillin (MRSA) often show resistance to other classes of antibiotics (multidrug resistance). The advancement of phage therapy against MRSA infections offers a promising alternative in the context of increasing antibiotic resistance. Therapeutic phages are easier to obtain and cheaper to produce than antibiotics. However, there is still a lack of standards to ensure the safe use of phages, including purification, dosage, means of administration, and the quantity of phages used. Some bacteria have developed defense mechanisms against phages. The use of phage cocktails or the combination of antibiotics and phages is preferred. For personalized therapy, it is essential to set up large collections to enable phage selection. In the future, the fight against MRSA strains using phages should be based on a multidisciplinary approach, including molecular biology and medicine. Other therapies in the fight against MRSA strains include the use of endolysin antimicrobial peptides (including defensins and cathelicidins). Researchers’ activities also focus on the potential use of plant extracts, honey, propolis, alkaloids, and essential oils. To date, no vaccine has been approved against S. aureus strains. Full article

African Swine Fever (ASF) is a highly contagious viral disease threatening the global pig industry. Currently, only two gene-deleted live attenuated vaccines are approved, exclusively in Vietnam, and their long-term effectiveness and safety are unproven, prompting the need for safer alternatives. This study assessed a cocktail of African Swine Fever Virus (ASFV) antigens delivered via a recombinant Newcastle Disease Virus (rNDV) vector against the genotype II ASFV-SY18. Antigens pB602L, pEP84R, and p22 (pKP177R) were selected based on virus neutralization and lymphocyte proliferation assays in mice and combined with capsid protein p72 (pB646L) for vaccination and challenge in pigs. The antigen cocktail delayed ASF symptoms by 3–4 days but did not prevent the lethal ASFV-SY18 infection. Significant ASFV-specific gamma interferon (IFN-γ) positive responses and NDV antibodies were detected post-inoculation, showing an induced immune response, though ASFV-specific p72 antibodies were absent. The cocktail did not cause cytokine imbalance, indicating the vector’s safety in pigs. Despite some delay in disease progression, the protection against genotype II ASFV was inadequate, underscoring the need to select more effective antigens and enhance immune responses for virus-vectored vaccines. Full article

Background: Toxoplasma gondii can cause congenital infections and abortions in humans. TgIST and TgNSM play critical roles in intracellular cyst formation and chronic infection. However, no studies have explored their potential to induce protective immunity against T. gondii infection. Objective: To evaluate the immune efficacy of DNA vaccines encoding TgNSM and TgIST genes against T. gondii infection, using the acute and chronic ME49 strain (Type II). Methods: DNA vaccines, including eukaryotic plasmids pVAX-IST and pVAX-NSM, were constructed. A cocktail DNA vaccine combining these two genes was formulated. The expression and immunogenicity were determined using the indirect immunofluorescence assay (IFA). Mice were immunized with DNA vaccines encoding either TgIST or TgNSM, as well as with the cocktail DNA vaccine. Humoral and cellular immune responses were analyzed by detecting antibody levels, cytotoxic T cell (CTL) responses, cytokines, and lymphocyte surface markers. Mouse survival and brain cyst counts were assessed 1 to 2 months post-vaccination in experimental toxoplasmosis models. The adjuvant efficacy of plasmid pVAX-IL-36γ in enhancing DNA vaccine-induced protective immunity was also evaluated. Results: DNA immunization with pVAX-IST and pVAX-NSM elicited strong humoral and cellular immune responses, characterized by increased Toxoplasma-specific IgG2a titers, Th1 responses (including production of IFN-γ, IL-2, IL-12p40, and IL-12p70), and cell-mediated activity with elevated frequencies of CD8+ and CD4+ T cells, and CTL responses. This provided significant protective efficacy against acute and chronic T. gondii infection. Mice immunized with the two-gene cocktail (pVAX-IST + pVAX-NSM) showed greater protection than those immunized with single-gene vaccines. Co-administration of the molecular adjuvant pVAX-IL-36γ further enhanced the protective immunity induced by the cocktail DNA vaccine. Conclusions: TgIST and TgNSM induce effective immunity against T. gondii infection, making them promising vaccine candidates against toxoplasmosis. Additionally, IL-36γ is a promising genetic adjuvant that enhances protective immunity in a vaccine setting against T. gondii, and it should be evaluated in strategies against other apicomplexan parasites. Full article

The development of serum-free media (SFM) is critical to advance cell culture techniques used in viral vaccine production and address the ethical concerns and contamination risks associated with fetal bovine serum (FBS). This study evaluated the effects of marine microalgal extracts and growth factor cocktails on the activity of Madin-Darby canine kidney (MDCK) and Vero cells. Five marine microalgal species were used: Spirulina platensis (SP), Dunaliella salina (DS), Haematococcus pluvialis (HP), Nannochloropsis salina (NS), and Tetraselmis sp. (TS). DS and SP extracts significantly increased the proliferation rate of both MDCK and Vero cells. DS had a proliferation rate of 149.56% and 195.50% in MDCK and Vero cells, respectively, compared with that in serum-free medium (SFM). Notably, DS and SP extracts significantly increased superoxide dismutase (SOD) activity, which was 118.61% in MDCK cells and 130.08% in Vero cells for DS, and 108.72% in MDCK cells and 125.63% in Vero cells for SP, indicating a reduction in intracellular oxidative stress. Marine microalgal extracts, especially DS and SP, are feasible alternatives to FBS in cell culture as they promote cell proliferation, ensure safety, and supply essential nutrients while reducing oxidative stress. Full article

Influenza, often referred to as the flu, is an extremely contagious respiratory illness caused by influenza viruses, impacting populations globally with significant health consequences annually. A hallmark of influenza is its seasonal patterns, influenced by a mix of geographic, evolutionary, immunological, and environmental factors. Understanding these seasonal trends is crucial for informing public health decisions, including the planning of vaccination campaigns and their formulation. In our study, we introduce a genotype-structured infectious disease model for influenza transmission, immunity, and evolution. In this model, the population of infected individuals is structured according to the virus they harbor. It considers a symmetrical fitness landscape where the influenza A and B variants are considered. The model incorporates the effects of population immunity, climate, and epidemic heterogeneity, which makes it suitable for investigating influenza seasonal dynamics. We parameterize the model to the genomic surveillance data of flu in the US and use numerical simulations to elucidate the scenarios that result in the alternating or consecutive prevalence of flu variants. We show that the speed of virus evolution determines the alternation and co-circulation patterns of seasonal influenza. Our simulations indicate that slow immune waning reduces how often variants change, while cross-immunity regulates the co-circulation of variants. The framework can be used to predict the composition of future influenza outbreaks and guide the development of cocktail vaccines and antivirals that mitigate influenza in both the short and long term. Full article

Periodontal disease (PD) is caused by microbial dysbiosis and accompanying adverse inflammatory responses. Due to its high incidence and association with various systemic diseases, disease-modifying treatments that modulate dysbiosis serve as promising therapeutic approaches. In this study, to simulate the pathophysiological situation, we established a “temporary ligature plus oral infection model” that incorporates a temporary silk ligature and oral infection with a cocktail of live Tannerella forsythia (Tf), Pophyromonas gingivalis (Pg), and Fusobacterium nucleatum (Fn) in mice and tested the efficacy of a new trivalent mucosal vaccine. It has been reported that Tf, a red complex pathogen, amplifies periodontitis severity by interacting with periodontopathic bacteria such as Pg and Fn. Here, we developed a recombinant mucosal vaccine targeting a surface-associated protein, BspA, of Tf by genetically combining truncated BspA with built-in adjuvant flagellin (FlaB). To simultaneously induce Tf-, Pg-, and Fn-specific immune responses, it was formulated as a trivalent mucosal vaccine containing Tf-FlaB-tBspA (BtB), Pg-Hgp44-FlaB (HB), and Fn-FlaB-tFomA (BtA). Intranasal immunization with the trivalent mucosal vaccine (BtB + HB + BtA) prevented alveolar bone loss and gingival proinflammatory cytokine production. Vaccinated mice exhibited significant induction of Tf-tBspA-, Pg-Hgp44-, and Fn-tFomA-specific IgG and IgA responses in the serum and saliva, respectively. The anti-sera and anti-saliva efficiently inhibited epithelial cell invasion by Tf and Pg and interfered with biofilm formation by Fn. The flagellin-adjuvanted trivalent mucosal vaccine offers a novel method for modulating dysbiotic bacteria associated with periodontitis. This approach leverages the adjuvant properties of flagellin to enhance the immune response, aiming to restore a balanced microbial environment and improve periodontal health. Full article

The suboptimal performance of rotavirus (RV) vaccines in developing countries and in animals necessitates further research on the development of novel therapeutics and control strategies. To initiate infection, RV interacts with cell-surface O-glycans, including histo-blood group antigens (HBGAs). We have previously demonstrated that certain non-pathogenic bacteria express HBGA^- like substances (HBGA⁺) capable of binding RV particles in vitro. We hypothesized that HBGA⁺ bacteria can bind RV particles in the gut lumen protecting against RV species A (RVA), B (RVB), and C (RVC) infection in vivo. In this study, germ-free piglets were colonized with HBGA⁺ or HBGA^- bacterial cocktail and infected with RVA/RVB/RVC of different genotypes. Diarrhea severity, virus shedding, immunoglobulin A (IgA) Ab titers, and cytokine levels were evaluated. Overall, colonization with HBGA⁺ bacteria resulted in reduced diarrhea severity and virus shedding compared to the HBGA^- bacteria. Consistent with our hypothesis, the reduced severity of RV disease and infection was not associated with significant alterations in immune responses. Additionally, colonization with HBGA⁺ bacteria conferred beneficial effects irrespective of the piglet HBGA phenotype. These findings are the first experimental evidence that probiotic performance in vivo can be improved by including HBGA⁺ bacteria, providing decoy epitopes for broader/more consistent protection against diverse RVs. Full article