Adjuvanted Vaccine Research Articles

Safety of Adjuvanted Recombinant Herpes Zoster Virus Vaccination in Fragile Populations: An Observational Real-Life Study.

Vaccination is the most effective strategy for preventing infectious diseases and related complications, and proving its efficacy is crucial for its success and adherence, especially for newly introduced vaccines, such as adjuvanted recombinant herpes zoster virus vaccination (RZV). In this observational real-life study, we recorded adverse effects following immunization (AEFIs) after RZV administration in frail populations. A total of 271 subjects underwent RZV at Vaccination Center, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy. Most subjects were solid organ transplant recipients (kidney, 77.1%; liver, 4.8%). Demographics, clinical data, and AEFIs (type, duration, and medications used) were recorded. Overall, 37% of participants reported at least one AEFI following the first dose, predominantly pain at the injection site (60%), while 41% did so after the second dose (pain at the injection site in 62% of cases). Medications were more frequently used for AEFI treatment after the second dose (28%) rather than after the first dose (13%) (p = 0.01). After stratification by sex, females experienced AEFIs more frequently than males, particularly local skin reactions. Our study added evidence of safety and tolerability of the adjuvanted recombinant RZV in frail adults.

Zoster vaccination

Herpes zoster (HZ) is a sequela of the reactivation of a latent varicella zoster virus (VZV) infection of the sensory dorsal root ganglia and cranial nerves due to adecrease in specific Tcell-mediated immunity as aresult of immunosenescence, immunodeficiency diseases, e.g., human immunodeficiency virus (HIV) infection or immunosuppressive therapy. The disease burden of HZ greatly increases with age; however, younger patients with, e.g., inflammatory rheumatic diseases, also have an increased risk of HZ, which is higher under certain immunosuppressive drugs, e.g., Janus kinase (JAK) inhibitors or glucocorticoids. The risk of complications, e.g., postherpetic neuralgia (PHN) is also increased in this patient group. Of the two vaccines licensed in Germany, the Standing Committee on Vaccination (STIKO) at the Robert Koch Institute recommends the recombinant adjuvanted HZ subunit vaccine for the standard vaccination of all persons ≥ 60years and for persons ≥ 50years with an increased HZ risk for prevention of HZ and PNH due to its better efficacy and longer duration of effectiveness. Clinical trials have demonstrated a 90-97% efficacy in preventing HZ in immune healthy adults aged ≥ 50 years, with a much higher reactogenicity in the vaccine group compared to placebo. Adequate efficacy, immunogenicity and safety have also been demonstrated in clinical trials in immunocompromised and immunosuppressed patients. An extension of the STIKO vaccination recommendation to all adults with an increased HZ risk in line with the approval would be welcome.

Dual-functional emulsifier based nano-emulsion adjuvant effectively enhanced immunogenicity of recombinant respiratory syncytial virus vaccine in mice

Oil-in-water nano-emulsion adjuvant (NEA) has been utilized for many years in the development of subunit or/and recombinant vaccines. Nevertheless, worries have been expressed about the safety and potential biological activities of the emulsifier. Herein, tocopheryl polyethylene glycol 1000 succinate (TPGS), which acts not only as an emulsifier but also as an immunostimulant, was used for the preparation of NEA. Benefiting from the hydrophilic-hydrophobic nature of TPGS, NEA possess a homogeneous structure with an extremely narrow size distribution (approximately 160 nm in diameter, polydispersity index <0.15), and exhibits excellent stability over 6 months under test conditions. When such an NEA was used with a recombinant respiratory syncytial virus (RSV) vaccine, the adjuvanted vaccine induced enhanced humoral and cellular immunity in mice compared to the non-adjuvanted vaccine. This is the initial documented finding of TPGS adjuvanticity in an intramuscularly injected vaccine. Furthermore, the TPGS-based NEA showed elevated adjuvant potency compared to the MF59-like emulsion adjuvant assessed. These results imply the potential of NEA as an alternative adjuvant for developing recombinant vaccines with enhanced immunity.

Maternal Immunization with Adjuvanted Recombinant Receptor-Binding Domain Protein Provides Immune Protection against SARS-CoV-2 in Infant Monkeys.

Maternal vaccinations administered prior to conception or during pregnancy enhance the immune protection of newborn infants against many pathogens. A feasibility experiment was conducted to determine if monkeys can be used to model the placental transfer of maternal antibody against SARS-CoV-2. Six adult rhesus monkeys were immunized with adjuvanted recombinant-protein antigens comprised of receptor-binding domain human IgG1-Fc fusion proteins (RBD-Fc) containing protein sequences from the ancestral-Wuhan or Gamma variants. The female monkeys mounted robust and sustained anti-SARS-CoV-2 antibody responses. Blood samples collected from their infants after delivery verified prenatal transfer of high levels of spike-specific IgG, which were positively correlated with maternal IgG titers at term. In addition, an in vitro test of ACE2 neutralization indicated that the infants' IgG demonstrated antigen specificity, reflecting prior maternal immunization with either Wuhan or Gamma-variant antigens. All sera showed stronger ACE2-RBD binding inhibition when variants in the assay more closely resembled the vaccine RBD sequence than with more distantly related variants (i.e., Delta and Omicron). Monkeys are a valuable animal model for evaluating new vaccines that can promote maternal and infant health. Further, the findings highlight the enduring nature and safety of the immune protection elicited by an adjuvanted recombinant RBD-Fc vaccine.

Lipo-pam™ adjuvanted herpes zoster vaccine induces potent gE-specific cellular and humoral immune responses

Herpes zoster (HZ), also known as shingles, is caused by the reactivation of latent varicella-zoster virus (VZV). Decreased VZV-specific T-cell immune responses significantly contribute to the development of HZ. Shingrix is a recombinant zoster vaccine that is currently used to prevent HZ. However, Shingrix has high reactogenicity and pain at the injection site due to QS21, one of the adjuvant components. In this study, we developed a new herpes zoster vaccine formulation called CVI-VZV-001, containing gE protein and a novel liposome-based adjuvant Lipo-pam™, which consists of two TLR agonists. We evaluated the immunogenicity of CVI-VZV-001 in mouse and rabbit models. CVI-VZV-001 elicited robust gE-specific T-cell immune responses and gE-specific antibody production. Specifically, CVI-VZV-001 induced polyfunctional CD4+ T cell populations that secrete multiple cytokines. Furthermore, CVI-VZV-001 sustained the gE-specific immune responses for up to six months after immunization. To ensure CVI-VZV-001’s safety for further development, we conducted a good laboratory practice (GLP) toxicity test, which confirmed that CVI-VZV-001 is safe for use. At present, CVI-VZV-001 is undergoing phase I clinical trials. This study suggests that CVI-VZV-001 can be a potent candidate for the HZ vaccine with high immunogenicity and safety.

Intranasal Delivery of Quillaja brasiliensis Saponin-Based Nanoadjuvants Improve Humoral Immune Response of Influenza Vaccine in Aged Mice.

Increasing the effectiveness of vaccines against respiratory viruses is particularly relevant for the elderly, since they are prone to develop serious infections due to comorbidities and the senescence of the immune system. The addition of saponin-based adjuvants is an interesting strategy to increase the effectiveness of vaccines. We have previously shown that ISCOM matrices from Q. brasiliensis (IMXQB) are a safe and potent adjuvant. In this study, we evaluated the use of IMXQB as an adjuvant for the seasonal trivalent influenza vaccine (TIV) in an aged mice model. Herein, we show that subcutaneous injection of the adjuvanted vaccine promoted higher titers of IgM, IgG (and isotypes), and serum hemagglutination inhibition titers (HAI). Notably, aged mice immunized by intranasal route also produced higher IgG (and isotypes) and IgA titers up to 120 days after priming, as well as demonstrating an improvement in the HAI antibodies against the TIV. Further, experimental infected aged mice treated once with sera from adult naïve mice previously immunized with TIV-IMXQB subcutaneously successfully controlled the infection. Overall, TIV-IMXQB improved the immunogenicity compared to TIV by enhancing systemic and mucosal immunity in old mice conferring a faster recovery after the H1N1pdm09-like virus challenge. Thus, IMXQB nanoparticles may be a promising platform for next-generation viral vaccines.

Evaluation of the immune responses of biological adjuvant bivalent vaccine with three different insertion modes for ND and IBD

ABSTRACT Infectious bursal disease (IBD) is a widespread problem in the poultry industry, and vaccination is the primary preventive method. However, moderately virulent vaccines may damage the bursa, necessitating the development of a safe and effective vaccine. The Newcastle disease virus (NDV) has been explored as a vector for vaccine development. In this study, reverse genetic technology was used to obtain three recombinant viruses, namely, rClone30-VP2L (P/M)-chGM-CSF (NP), rClone30-chGM-CSF (P/M)-VP2L (NP), and rClone30-VP2L-chGM-CSF (P/M). Animal experiments showed that the three biological adjuvant bivalent vaccines effectively increased anti-NDV and anti-infectious bursal disease virus (IBDV) titres, enhancing both humoral and cellular immune responses in chickens without leading to any harm. Amongst the three biological adjuvant bivalent vaccines, the rClone30-chGM-CSF (P/M)-VP2L (NP) group had higher levels of anti-NDV antibodies at 14 days after the first immunization and stimulated a greater humoral immune response in 7–10 days. While, the rClone30-VP2L (P/M)-chGM-CSF (NP) group was the most effective in producing a higher level of IBDV antibody response. In conclusion, these three vaccines can induce immune responses more rapidly and effectively, streamline production processes, be cost-effective, and provide a new avenue for the development of Newcastle disease (ND) and IBD bivalent vaccines

Safety and Immunogenicity of Respiratory Syncytial Virus Prefusion F Protein Vaccine when Co-administered with Adjuvanted Seasonal Quadrivalent Influenza Vaccine in Older Adults: A Phase 3 Randomized Trial.

We evaluated co-administration of adjuvanted seasonal quadrivalent influenza vaccine (FLU-aQIV) and respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVPreF3 OA) in ≥65-year-olds. This phase 3, open-label trial randomized ≥65-year-olds to receive FLU-aQIV and RSVPreF3 OA concomitantly (Co-Ad) or sequentially, 1 month apart (Control). Primary objectives were to demonstrate the non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration in terms of hemagglutination inhibition (HI) titers for each FLU-aQIV strain and RSV-A and RSV-B neutralization titers, 1 month post-vaccination. Reactogenicity and safety were also assessed. Overall, 1045 participants were vaccinated (Co-Ad: 523; Control: 522). Non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration was demonstrated in terms of HI titers for the A/Victoria(H1N1), B/Victoria, and B/Yamagata influenza strains and RSV-A neutralization titers (upper limits [ULs] of 95% confidence intervals [CIs] for adjusted geometric mean titer [GMT] ratios [Control/Co-Ad] ≤1.50) but not for A/Darwin(H3N2) HI titers (95% CI UL = 1.53). The immune response to A/Darwin(H3N2) was further assessed post-hoc using a microneutralization assay; the post-vaccination adjusted GMT ratio (Control/Co-Ad) was 1.23 (95% CI: 1.06-1.42, ie, UL ≤1.50), suggesting an adequate immune response to A/Darwin(H3N2) following co-administration. RSV-B neutralization titers were comparable between groups (95% CI UL for adjusted GMT ratio ≤1.50). Solicited adverse events were mostly mild or moderate and transient; unsolicited and serious adverse event rates were balanced between groups. Adjuvanted FLU-aQIV and RSVPreF3 OA had acceptable reactogenicity/safety profiles when co-administered in ≥65-year-olds, without clinically relevant interference with the immune responses to either vaccine. NCT05568797.

Heterologous Prime-Boost Immunization Strategies Using Varicella-Zoster Virus gE mRNA Vaccine and Adjuvanted Protein Subunit Vaccine Triggered Superior Cell Immune Response in Middle-Aged Mice.

Heterologous immunization using different vaccine platforms has been demonstrated as an efficient strategy to enhance antigen-specific immune responses. In this study, we performed a head-to-head comparison of both humoral and cellular immune response induced by different prime-boost immunization regimens of mRNA vaccine and adjuvanted protein subunit vaccine against varicella-zoster virus (VZV) in middle-aged mice, aiming to get a better understanding of the influence of vaccination schedule on immune response. VZV glycoprotein (gE) mRNA was synthesized and encapsulated into SM-102-based lipid nanoparticles (LNPs). VZV-primed middle-aged C57BL/6 mice were then subjected to homologous and heterologous prime-boost immunization strategies using VZV gE mRNA vaccine (RNA-gE) and protein subunit vaccine (PS-gE). The antigen-specific antibodies were evaluated using enzyme-linked immunosorbent assay (ELISA) analysis. Additionally, cell-mediated immunity (CMI) was detected using ELISPOT assay and flow cytometry. Besides, in vivo safety profiles were also evaluated and compared. The mRNA-loaded lipid nanoparticles had a hydrodynamic diameter of approximately 130 nm and a polydispersity index of 0.156. Total IgG antibody levels exhibited no significant differences among different immunization strategies. However, mice received 2×RNA-gE or RNA-gE>PS-gE showed a lower IgG1/IgG2c ratio than those received 2×PS-gE and PS-gE> RNA-gE. The CMI response induced by 2×RNA-gE or RNA-gE>PS-gE was significantly stronger than that induced by 2×PS-gE and PS-gE> RNA-gE. The safety evaluation indicated that both mRNA vaccine and protein vaccine induced a transient body weight loss in mice. Furthermore, the protein vaccine produced a notable inflammatory response at the injection sites, while the mRNA vaccine showed no observable inflammation. The heterologous prime-boost strategy has demonstrated that an mRNA-primed immunization regimen can induce a better cell-mediated immune response than a protein subunit-primed regimen in middle-aged mice. These findings provide valuable insights into the design and optimization of VZV vaccines with the potentials to broaden varicella vaccination strategies in the future.

Comparison of Post-Vaccination Cellular Immune Response in Patients with Common Variable Immune Deficiency.

The problem of identifying vaccine-specific T-cell responses is still a matter of debate. Currently, there are no universal, clearly defined, agreed upon criteria for assessing the effectiveness of vaccinations and their immunogenicity for the cellular component of immunity, even for healthy people. But for patients with inborn errors of immunity (IEI), especially those with antibody deficiencies, evaluating cellular immunity holds significant importance. To examine the effect of one and two doses of inactivated adjuvanted subunit influenza vaccines on the expression of endosomal Toll-like receptors (TLRs) on the immune cells and the primary lymphocyte subpopulations in patients with common variable immunodeficiency (CVID). During 2018-2019, six CVID patients received one dose of a quadrivalent adjuvanted influenza vaccine; in 2019-2020, nine patients were vaccinated with two doses of a trivalent inactivated influenza vaccine. The proportion of key lymphocyte subpopulations and expression levels of TLRs were analyzed using flow cytometry with monoclonal antibodies. No statistically significant alterations in the absolute values of the main lymphocyte subpopulations were observed in CVID patients before or after vaccination with the different immunization protocols. However, after vaccination, a higher expression of TLR3 and TLR9 in granulocytes, monocytes, and lymphocytes was found in those patients who received two vaccine doses rather than one single dose. This study marks the first instance of using a simultaneous two-dose vaccination, which is associated with an elevated level of TLR expression in the immune cells. Administration of the adjuvanted vaccines in CVID patients appears promising. Further research into their impact on innate immunity and the development of more effective vaccination regimens is warranted.

Licensed H5N1 vaccines generate cross-neutralizing antibodies against highly pathogenic H5N1 clade 2.3.4.4b influenza virus.

The emergence of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b viruses and their transmission to dairy cattle and animals, including humans, poses a major global public health threat. Therefore, the development of effective vaccines and therapeutics against H5N1 clade 2.3.4.4b virus is considered a public health priority. In the United States, three H5N1 vaccines derived from earlier strains of HPAI H5N1 (A/Vietnam, clade 1, and A/Indonesia, clade 2.1) virus, with (MF59 or AS03) or without adjuvants, are licensed and stockpiled for pre-pandemic preparedness, but whether they can elicit neutralizing antibodies against circulating H5N1 clade 2.3.4.4b viruses is unknown. In this study, we evaluated the binding, hemagglutination inhibition and neutralizing antibody response generated after vaccination of adults with the three licensed vaccines. Individuals vaccinated with the two adjuvanted licensed H5N1 vaccines generated cross-reactive binding and cross-neutralizing antibodies against the HPAI clade 2.3.4.4b A/Astrakhan/3212/2020 virus. Seroconversion rates of 60-95% against H5 clade 2.3.4.4b were observed after two doses of AS03-adjuvanted-A/Indonesia or three doses of MF59-adjuvanted-A/Vietnam vaccine. These findings suggest that the stockpiled US-licensed adjuvanted H5N1 vaccines generate cross-neutralizing antibodies against circulating HPAI H5N1 clade 2.3.4.4b in humans and may be useful as bridging vaccines until updated H5N1 vaccines become available.

Reassortment incompetent live attenuated and replicon influenza vaccines provide improved protection against influenza in piglets

Swine influenza A viruses (swIAV) cause an economically important respiratory disease in modern pig production. Continuous virus transmission and antigenic drift are difficult to control in enzootically infected pig herds. Here, antibody-positive piglets from a herd enzootically infected with swIAV H1N2 (clade 1 A.3.3.2) were immunized using a homologous prime-boost vaccination strategy with novel live attenuated influenza virus (LAIV) based on a reassortment-incompetent bat influenza-swIAV chimera or a vesicular stomatitis virus-based replicon vaccine. Challenge infection of vaccinated piglets by exposure to H1N2 swIAV-infected unvaccinated seeder pigs showed that both LAIV and replicon vaccine markedly reduced virus replication in the upper and lower respiratory tract, respectively, compared to piglets immunized with commercial heterologous or autologous adjuvanted whole-inactivated virus vaccines. Our novel vaccines may aid in interrupting continuous IAV transmission chains in large enzootically infected pig herds, improve the health status of the animals, and reduce the risk of zoonotic swIAV transmission.

Immunoprotective efficacy of aqueous monovalent vaccine, turmeric (curcuma longa) rhizome and soursop (annona muricata) leaves against Pseudomonas aeruginosa infection in African sharptooth catfish (clarias gariepinus) fingerlings

ABSTRACT This study evaluated the efficacy of aqueous monovalent vaccine (AqMV) and adjuvant monovalent vaccine (AdMV), different levels of soursop leaves (SL), and turmeric rhizome (TR) on growth performance, immune response, and disease resistance of African sharptooth catfish (Clarias gariepinus) fingerlings against Pseudomonas aeruginosa. The experimental diet consists of control (without vaccine, soursop leaves and turmeric rhizome), AqMV2, AdMV3, TR4 (0.5), TR5 (1.0), TR6 (2.0), SL7 (0.5), SL8 (1.0) and SL9 (2.0). Fish were exposed to 4.85 log10 CFU/ml P. aeruginosa of 24 h old culture intraperitoneally after feeding trial with relative level of protection recorded at 28 days of post-infection. The results revealed that fish fed with treated diets showed increased (p < .05) weight gain, feed conversion ratio, nitrogen metabolism, white blood cell, globulin, total protein and blood performance and better relative level of protection compared to the control. The microbial loads in fish samples (muscle, spleen and kidney) were reduced (p < .05) in the treatments when compared to the control at 4-week post-infection. These results suggest that inactivated aqueous monovalent vaccine, soursop leaves and turmeric rhizome could be effective against P. aeruginosa infection in fish farming.

Identifying transcriptomic profiles in ovine spleen after repetitive vaccination.

Aluminum hydroxide has long been employed as a vaccine adjuvant for its safety profile, although its precise mechanism of action remains elusive. In this study, we investigated the transcriptomic responses in sheep spleen following repetitive vaccination with aluminum adjuvanted vaccines and aluminum hydroxide alone. Notably, this work represents the first exploration of the sheep spleen transcriptome in such conditions. Animals were splitted in 3 treatment groups: vaccine group, adjuvant alone group and control group. A total of 18 high-depth RNA-seq libraries were sequenced, resulting in a rich dataset which also allowed isoform-level analysis. The comparisons between vaccine-treated and control groups (V vs C) as well as between vaccine-treated and adjuvant-alone groups (V vs A) revealed significant alterations in gene expression profiles, including protein coding genes and long non-coding RNAs. Among the differentially expressed genes, many were associated with processes such as endoplasmic reticulum (ER) stress, immune response and cell cycle. The analysis of co-expression modules further indicated a correlation between vaccine treatment and genes related to ER stress and unfolded protein response. Surprisingly, adjuvant-alone treatment had little impact on the spleen transcriptome. Additionally, the role of alternative splicing in the immune response was explored. We identified isoform switches in genes associated with immune regulation and inflammation, potentially influencing protein function. In conclusion, this study provides valuable insights into the transcriptomic changes in sheep spleen following vaccination with aluminum adjuvanted vaccines and aluminum hydroxide alone. These findings shed light on the molecular mechanisms underlying vaccine-induced immune responses and emphasize the significance of antigenic components in aluminum adjuvant mechanism of action. Furthermore, the analysis of alternative splicing revealed an additional layer of complexity in the immune response to vaccination in a livestock species.

Protection against experimental cryptococcosis elicited by Cationic Adjuvant Formulation 01-adjuvanted subunit vaccines.

The fungal infection, cryptococcosis, is responsible for >100,000 deaths annually. No licensed vaccines are available. We explored the efficacy and immune responses of subunit cryptococcal vaccines adjuvanted with Cationic Adjuvant Formulation 01 (CAF01). CAF01 promotes humoral and T helper (Th) 1 and Th17 immune responses and has been safely used in human vaccine trials. Four subcutaneous vaccines, each containing single recombinant Cryptococcus neoformans protein antigens, partially protected mice from experimental cryptococcosis. Protection increased, up to 100%, in mice that received bivalent and quadrivalent vaccine formulations. Vaccinated mice that received a pulmonary challenge with C. neoformans had an influx of leukocytes into the lung including robust numbers of polyfunctional CD4+ T cells which produced interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), and interleukin (IL)-17 upon ex vivo antigenic stimulation. Cytokine-producing lung CD8+ T cells were also found, albeit in lesser numbers. A significant, durable IFNγ response was observed in the lungs, spleen, and blood. Moreover, IFNγ secretion following ex vivo stimulation directly correlated with fungal control in the lungs. Thus, we have developed multivalent cryptococcal vaccines which protect mice from experimental cryptococcosis using an adjuvant which has been safely tested in humans. These preclinical studies suggest a path towards human cryptococcal vaccine trials.

Malaria transmission blocking activity of Anopheles stephensi alanyl aminopeptidase N antigen formulated with MPL, CpG, and QS21 adjuvants.

Malaria, a preventive and treatable disease, is still responsible for annual deaths reported in most tropical regions, principally in sub-Saharan Africa. Subunit recombinant transmission-blocking vaccines (TBVs) have been proposed as promising vaccines to succeed in malaria elimination and eradication. Here, a provisional study was designed to assess the immunogenicity and functional activity of alanyl aminopeptidase N (APN1) of Anopheles stephensi, as a TBV candidate, administered with MPL, CpG, and QS21 adjuvants in the murine model. The mouse groups were immunized with recombinant APN1 (rAPN1) alone or formulated with CpG, MPL, QS-21, or a combination of adjuvants (CMQ), and the elicited immune responses were evaluated after the third immunization. The standard membrane feeding assay (SMFA) measured the functional activity of antibodies against bacterial-expressed APN1 protein in adjuvanted vaccine groups on transmission of P. falciparum (NF54) to An. stephensi mosquitoes. Evaluation of mice vaccinated with rAPN1 formulated with distinct adjuvants manifested a significant increase in the high-avidity level of anti-APN1 IgG and IgG subclasses; however, rAPN1 induced the highest level of high-avidity anti-APN1 IgG1, IgG2a, and IgG2b antibodies in the immunized vaccine group 5 (APN1/CMQ). In addition, vaccine group 5 (receiving APN1/CMQ), had still the highest level of anti-APN1 IgG antibodies relative to other immunized groups after six months, on day 180. The SMFA data indicates a trend towards higher transmission-reducing activity in groups 2 and 5, which received the antigen formulated with CpG or a combination of three adjuvants. The results have shown the capability of admixture to stimulate high-affinity and long-lasting antibodies against the target antigen to hinder Plasmodium parasite development in the mid-gut of An. stephensi. The attained results authenticated APN1/CMQ and APN1/CpG as a potent APN1-based TBV formulation which will be helpful in designing a vaccine in the future.

Widespread Myalgia and Chronic Fatigue: Phagocytes from Macrophagic Myofasciitis Patients Exposed to Aluminum Oxyhydroxide-Adjuvanted Vaccine Exhibit Specific Inflammatory, Autophagic, and Mitochondrial Responses.

(1) Background: Macrophagic myofasciitis (MMF) is an inflammatory histopathological lesion demonstrating long-term biopersistence of vaccine-derived aluminum adjuvants within muscular phagocytic cells. Affected patients suffer from widespread myalgia and severe fatigue consistent with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a poorly understood disorder suspected to result from chronic immune stimulation by infectious and inorganic particles. (2) Methods: In this study we determined the immuno-metabolic properties of MMF phagocytic cells compared to controls, at rest and upon exposure to aluminum oxyhydroxide adjuvant, with or without adsorbed antigens, using protein quantification and an oxygen consumption assay. (3) Results: MMF and control cells similarly internalized the adjuvant and vaccine but MMF cells specifically expressed Rubicon and Nox2, two molecules unique to the LC3-associated phagocytosis (LAP) machinery, a non-canonical autophagic pathway able to downregulate canonical autophagy. MMF cells exhibited an altered inflammatory secretome, producing more pain-inducing CXC chemokines and less TNF-α than controls, consistent with chronic myalgia and exhaustion of the immune system previously documented in ME/CFS. MMF cells exhibited mitochondrial metabolism dysfunction, with exacerbated reaction to adjuvanted vaccine, contrasting with limited spare respiratory capacity and marked proton leak weakening energy production. (4) Conclusions: MMF phagocytes seemingly use LAP to handle aluminum oxyhydroxide vaccine particles, secrete pain-inducing molecules, and exhibit exacerbated metabolic reaction to the vaccine with limited capacity to respond to ongoing energetic requests.

Results of a clinical study of the influenza tetravalent inactivated subunit adjuvant vaccine Grippol Quadrivalent in children aged 6 months to 5 years (inclusive)

The article presents the results of a clinical investigation on the administration of the Grippol Quadrivalent vaccine (influenza tetravalent inactivated subunit adjuvant vaccine) in children from 6 months to 5 years old. The vaccine has demonstrated no less effectiveness in comparison with the Grippol plus vaccine (influenza trivalent inactivated polymer-subunit vaccine).comparable results were obtained for all evaluated indicators of immunological efficacy against matching strains of the influenza virus, while for additional strain B (Yamagata line) there was a statistically significant difference in the increase in the immune response in the Grippol Quadrivalent group. The results of the assessment of the reactogenicity and frequency of systemic adverse events indicated a favorable and comparable safety profile of the vaccines Grippol Quadrivalent and Grippol plus in children from 6 months to 5 years old. The data obtained allowed us to conclude that the immunological efficacy of the Grippol Quadrivalent vaccine is no less when compared to the Grippol plus vaccine, as well as a comparable safety and reactogenicity profile. According to the results of the clinical investigation, on 08/04/2023, the Ministry of Health of the Russian Federation amended the “Instructions for the medical use of the drug”: Grippol Quadrivalent is indicated for children from the age of 6 months.

Determination of Deamidation in Adjuvanted Vaccine Antigens through Isoaspartic Acid Quantification.

Deamidation is a post-translational chemical modification that occurs within proteins and can be influenced by many factors, including temperature and pH. In vaccines, deamidation is considered undesirable as it may lead to changes in structure, function, stability, and immunogenicity. Detecting deamidation in vaccines, especially adjuvanted vaccines, can be challenging due to the lack of simple quantitative techniques. In this study, the quantification of isoaspartic acid (isoAsp) was used to assess deamidation in model antigens in the presence and absence of common vaccine adjuvants. This study shows that the detection of isoAsp was possible in the presence of various types of adjuvants with little to no interference. High levels of isoAsp were detected in thermally and pH-stressed adjuvanted vaccines, suggesting significant deamidation and highlighting the stability-indicating capabilities of the assay. The quantification of isoAsp in stability programs of a vaccine drug product could possibly find applications in product shelf-life determination, using thermal kinetic modeling to predict deamidation over time. The ability to detect deamidation early in vaccine development enhances process improvements and ultimately improves the vaccine's stability. To summarize, this paper describes a rapid and simple method to determine deamidation in adjuvanted vaccines. This method could be applicable to formulation development, stability assessment, or shelf-life determination.

Buccal Administration of a Zika Virus Vaccine Utilizing 3D-Printed Oral Dissolving Films in a Mouse Model.

Over the years, research regarding the Zika virus has been steadily increasing. Early immunization for ZIKV is a priority for preventing complications such as microencephaly and Guillain-Barré syndrome (GBS). Unlike traditional vaccination approaches, oral dissolving films (ODFs) or mucoadhesive film technology is an emerging, exciting concept that can be used in the field of pharmaceuticals for vaccine design and formulation development. This attractive and novel method can help patients who suffer from dysphagia as a complication of a disease or syndrome. In this study, we investigated a microparticulate Zika vaccine administered via the buccal route with the help of thin films or oral dissolving films (ODFs) with a prime dose and two booster doses two weeks apart. In vitro, the ODFs displayed excellent physiochemical properties, indicating that the films were good carriers for vaccine microparticles and biocompatible with the buccal mucosa. In vivo results revealed robust humoral (IgG, subtypes IgG1 and IgG2a) and T-cell responses (CD4+/CD8+) for ZIKV-specific immunity. Both the Zika MP vaccine and the adjuvanted Zika MP vaccine affected memory (CD45R/CD27) and intracellular cytokine (TNF-α and IL-6) expression. In this study, ZIKV vaccination via the buccal route with the aid of ODFs demonstrated great promise for the development of pain-free vaccines for infectious diseases.