Protective Immunity Research Articles

Abstract A014: Effects of senescence on the lung tumor microenvironment

Abstract Despite progress in screening and treatment, lung cancer remains the leading cause of cancer- related deaths worldwide. An overarching issue is the complexity and heterogeneous nature of the tumor microenvironment and eventual tumor spread. While aging is a key determinant, the relationship between aging and cancer is multi-faceted and extends beyond the accumulation of mutations. Therefore, a much-needed framework integrating the mechanistic principles that change with aging to drive neoplastic transformation beyond genetics will help us uncover predictive biomarkers that inform treatment decision-making and how we may use them to prevent, postpone, suppress tumor growth, and limit spread. Here, we investigate the role of age-related senescent cell accumulation in lung tumorigenesis and propose a potential strategy to delay tumor progression and spread by selectively targeting tumor-promoting senescent cells that arise with increasing age to sustain protective antitumor immunity. Citation Format: Luis Prieto. Effects of senescence on the lung tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A014.

Legal Protection For Advocates Who Are Considered Not In Good Faith For Alleged Obstruction Of Justice In Corruption Cases

Advocates as one of the professions in the field of law in their duty to defend clients both inside and outside the trial are equipped with privileges in the form of legal protection (immunity), but often these privileges are abused by advocates by obstruction of justice especially in cases of corruption crimes that aim to prevent clients from being investigated by Police Investigators, the Prosecutor's Office or the KPK. There are differences in the parameters of the assessment of good or bad ethics by an Advocate carried out by the Investigator so that it is considered to be an obstruction of justice so that there is a conflict between the legal norms contained in Article 16 of Law Number 18 of 2003 concerning Advocates and the reality that occurs in the field. The problem that causes advocates to be considered not to be good at obstructing justice in corruption cases is due to the absence of assessment parameters of advocates who are not in good faith and the absence of legal protection for advocates who are suspected of obstruction of justice, especially in corruption cases. The method used in this study is normative - empirical legal research, using a case approach, a legislative approach (statue approach) and a conceptual approach (Conceptual Approach). This study aims to examine the assessment parameters of advocates who do not have good faith against the suspicion of obstruction of justice by investigators and to find out the analysis of legal protection (immunity rights) owned by advocates who are considered to have no good faith by committing obstruction of justice, especially in cases of corruption. The results of this study are that the criteria for Advocates who are considered not in good faith are violations of the code of ethics, laws and regulations, oath or promise of Advocates as well as the value of feasibility and propriety. In addition, in order to create legal protection and certainty, a special institution such as the Advocate Honorary Council is needed which aims to determine whether the actions of the Advocate who are considered not to be in good faith are contrary to the etic code or laws and regulations or not.

The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor microenvironment and potentiates immunotherapy.

Histone deacetylase 6 (HDAC6) inhibition is associated with an increased pro-inflammatory tumor microenvironment and antitumoral immune responses. Here, we show that the HDAC6 inhibitor AVS100 (SS208) had an antitumoral effect in SM1 melanoma and CT26 colon cancer models and increased the efficacy of anti-programmed cell death protein 1 treatment, leading to complete remission in melanoma and increased response in colon cancer. AVS100 treatment increased pro-inflammatory tumor-infiltrating macrophages and CD8 effector T cells with an inflammatory and T cell effector gene signature. Acquired T cell immunity and long-term protection were evidenced as increased immunodominant T cell clones after AVS100 treatment. Last, AVS100 showed no mutagenicity, toxicity, or adverse effects in preclinical good laboratory practice studies, part of the package that has led to US Food and Drug Administration clearance of an investigational new drug application for initiating clinical trials. This would be a first-in-human combination therapy of pembrolizumab with HDAC6 inhibition for locally advanced or metastatic solid tumors.

Factors Predicting COVID-19 Vaccine Effectiveness and Longevity of Humoral Immune Responses

The COVID-19 pandemic, caused by SARS-CoV-2, prompted global efforts to develop vaccines to control the disease. Various vaccines, including mRNA (BNT162b2, mRNA-1273), adenoviral vector (ChAdOx1, Ad26.COV2.S), and inactivated virus platforms (BBIBP-CorV, CoronaVac), elicit high-titer, protective antibodies against the virus, but long-term antibody durability and effectiveness vary. The objective of this study is to elucidate the factors that influence vaccine effectiveness (VE) and the longevity of humoral immune responses to COVID-19 vaccines through a review of the relevant literature, including clinical and real-world studies. Here, we discuss the humoral immune response to different COVID-19 vaccines and identify factors influencing VE and antibody longevity. Despite initial robust immune responses, vaccine-induced immunity wanes over time, particularly with the emergence of variants, such as Delta and Omicron, that exhibit immune escape mechanisms. Additionally, the durability of the humoral immune responses elicited by different vaccine platforms, along with the identification of essential determinants of long-term protection—like pre-existing immunity, booster doses, hybrid immunity, and demographic factors—are critical for protecting against severe COVID-19. Booster vaccinations substantially restore neutralizing antibody levels, especially against immune-evasive variants, while individuals with hybrid immunity have a more durable and potent immune response. Importantly, comorbidities such as diabetes, cardiovascular disease, chronic kidney disease, and cancer significantly reduce the magnitude and longevity of vaccine-induced protection. Immunocompromised individuals, particularly those undergoing chemotherapy and those with hematologic malignancies, have diminished humoral responses and benefit disproportionately from booster vaccinations. Age and sex also influence immune responses, with older adults experiencing accelerated antibody decline and females generally exhibiting stronger humoral responses compared to males. Understanding the variables affecting immune protection is crucial to improving vaccine strategies and predicting VE and protection against COVID-19.

Mycobacterium tuberculosis Antigen Rv1471 Induces Innate Immune Memory and Adaptive Immunity against Infection.

Protein subunit vaccines form a key pipeline for developing novel tuberculosis (TB) vaccines. Mycobacterium tuberculosis (Mtb) contains approximately 4000 individual proteins. However, only approximately 100 have been evaluated as antigens in the clinical and preclinical stages of vaccine development. Trained immunity-targeting vaccines induce innate immune memory against heterologous infections and enhance antigen-specific adaptive immune responses. However, no trained immunity-targeting subunit TB vaccine has been reported yet. This study tested Rv1471, a thioredoxin secreted by Mtb, as a candidate TB vaccine antigen due to its capacity to stimulate mouse bone marrow-derived macrophages (BMDMs). Rv1471 induced functional and phenotypic maturation of BMDMs in vitro, reflected by the increased production of inflammatory cytokines and surface expression of co-stimulatory molecules. Transcription analysis of Rv1471-trained BMDMs indicated that innate immune memory was activated through pathways of Akt-mTOR-HIF-1α and aerobic glycolysis. Rv1471 also enhanced innate immune memory responses and protection against intracellular infections of different mycobacteria. In a murine model of TB, immunization with Rv1471 formulated with liposomal DDA/MPLA adjuvant produced robust antigen-specific multi-functional CD4+ and CD8+ T-cell immune responses and had substantial protective efficacy against Mtb challenge. Analysis of recall immunity showed that the Rv1471 subunit vaccine triggered robust T-cell immunity post Mtb infection. These findings support the development of an innate immune memory-targeting subunit TB vaccine to increase TB vaccine efficacy.

Recombinant chimeric horsepox virus (TNX-801) is attenuated relative to vaccinia virus strains in both in vitro and in vivo models.

Variola and monkeypox viruses are medically important pathogens that can cause fatal human disease. The two FDA-approved vaccines, ACAM-2000 and JYNNEOS, have important advantages and disadvantages. ACAM-2000 offers durable immunity; however, it has high adverse event rates. In contrast, JYNNEOS has a safer profile but requires two doses 4-weeks apart to achieve comparable immunity. Consequently, there is a need for vaccines offering durable immunity via single immunization with minimal adverse events. TNX-801 is a preclinical stage vaccine that can stimulate potent immunity via a single dose and provides protection against lethal mpox disease in the nonhuman primate model. Here, we show that TNX-801 is >10- to 1,000-fold attenuated in in vitro and in vivo models including human primary cells and immunocompromised murine models than vaccine strains utilized in smallpox eradication. The natural attenuation of TNX-801 and its ability to induce protective immunity via a single vaccination are promising and warrants further development.

Host Innate and Adaptive Immunity Against African Swine Fever Virus Infection

Africa swine fever virus (ASFV) is the causative agent of African swine fever (ASF), a highly contagious hemorrhagic disease that can result in up to 100% lethality in both wild and domestic swine, regardless of breed or age. The ongoing ASF pandemic poses significant threats to the pork industry and food security, with serious implications for the sanitary and socioeconomic system. Due to the limited understanding of ASFV pathogenesis and immune protection mechanisms, there are currently no safe and effective vaccines or specific treatments available, complicating efforts for prevention and control. This review summarizes the current understanding of the intricate interplay between ASFV and the host immune system, encompassing both innate and adaptive immune responses to ASFV infection, as well as insights into ASFV pathogenesis and immunosuppression. We aim to provide comprehensive information to support fundamental research on ASFV, highlighting existing gaps and suggesting future research directions. This work may serve as a theoretical foundation for the rational design of protective vaccines against this devastating viral disease.

The Immunomodulatory Effect of Intraperitoneal Injection of Licorice Extract on Giant Salamander

The effect of licorice extract on non-specific immune function of giant salamanders was studied by intraperitoneal injection. The results showed that the lysozyme activity in the drug group increased, and the lysozyme activity increased with the increase of dose. From the 7th day onwards, each sampling of the drug group showed significant differences compared to the control group (P<0.05). The phagocytic activity of macrophages in the drug group showed some fluctuations, but there was no significant difference compared to the control group. The white blood cell volume value of the high-dose group gradually increased in the first three samplings, and showed a significant difference compared to the control group at 14 days (P<0.05). It decreased slightly in the last two samplings, but was still higher than the control group at the same time. The spleen organ coefficient of the low-dose group was (0.7 ± 0.01) % at 28 days, higher than that of the control group (0.4 ± 0.05) %, and the high-dose group was (0.7 ± 0.07) % at 14 days, higher than that of the control group (0.4 ± 0.02) %. Both differences were significant (P<0.05). After the last sampling (28 days), artificial infection with <i>Aeromonas hydrophila</i> bacteria resulted in a mortality rate of 80% in the control group, 50% in the low-dose group, and 30% in the high-dose group, all lower than the control group. The drug group also had higher immune protection rates than the control group. The results indicate that intraperitoneal injection of licorice extract can improve the immune function and disease resistance of giant salamanders to a certain extent.

An engineered Japanese encephalitis virus mRNA-lipid nanoparticle immunization induces protective immunity in mice

IntroductionJapanese encephalitis virus (JEV) and Zika virus (ZIKV) pose a severe threat to human health. Our previous research results, as well as those of other research groups, indicated that antibodies (Abs) induced by JEV infection or JEV vaccine vaccination could enhance ZIKV infection in vitro and exacerbate the mortality of ZIKV-infected mice, vice versa, which is known as antibody-dependent enhancement (ADE). Although studies on other flaviviruses revealed that altering the amino acid residues located in the fusion loop (FL) of envelope (E) protein can reduce the level of flavivirus-cross-reactive Abs, thereby abating the ADE of heterologous flavivirus infection, it is unclear whether this strategy is equally applicable to JEV.MethodsIn this study, we constructed recombinant adenoviruses and nucleotide-modified mRNA-lipid nanoparticle (LNP) encoding JEV wild-type E protein or E protein mutant (designated as Ad5-JEV-EWT and Ad5-JEV-Emut; JEV-EWT mRNA-LNP, and JEV-Emut mRNA-LNP). We evaluated the immunogenicity of these vaccine candidates in mice and the capacity of vaccine-immune mouse sera to neutralize JEV infection or mediate ADE of ZIKV infection in vitro and in vivo.ResultsAd5-JEV-Emut or JEV-Emut mRNA-LNP immunization induced ZIKV-cross-reactive Ab response which is dramatically lower than that induced by Ad5-JEV-EWT and JEV-EWT mRNA-LNP, respectively. The levels of JEV-neutralizing Abs induced by Ad5-JEV-Emut or JEV-Emut mRNA-LNP are comparable to that induced by Ad5-JEV-EWT and JEV-EWT mRNA-LNP, respectively. The ability of Abs induced by Ad5-JEV-Emut to enhance ZIKV infection in vitro is attenuated as compared with that induced by Ad5-JEV-EWT. Moreover, JEV-Emut mRNA-LNP immunization elicited potent T cell response similar to JEV-EWT mRNA-LNP in mice. Mice immunized with each mRNA-LNP exhibited lower level of serum viral load than the mock-immunized mice post JEV challenge. Mice receiving JEV-EWT mRNA-LNP-immune mouse sera exhibited ADE post ZIKV challenge whereas passively transferred JEV-Emut mRNA-LNP-immune mouse sera did not lead to obvious ADE of ZIKV infection in recipient mice. Most importantly, maternally acquired Abs did not enhance the mortality of 1-day-old neonates born to JEV-Emut mRNA-LNP-immunized mice post ZIKV challenge.DiscussionThese results suggest that optimizing the FL sequence of JEV could significantly reduce the level of JEV/ZIKV-cross-reactive Abs and abrogate the ADE of ZIKV infection, providing a promising strategy to develop effective and safety JEV vaccine.

Engineered Immune Constructs Alter Antigen-Specific Immune Tolerance and Confer Durable Protection in Myelin-Driven Autoimmunity.

Autoimmune diseases are broadly characterized as a failure in immune tolerance. In multiple sclerosis (MS), autoreactive immune cells attack the protective myelin sheath lining neurons in the central nervous system. Therapeutic strategies that selectively and durably restore immune tolerance without broad immunosuppression are urgently needed for MS. Our lab has developed assemblies of immune constructs built entirely from myelin antigen (MOG35-55 or PLP139-151) and regulatory innate immune cues (GpG) using layer-by-layer self-assembly. Here, we present mechanistic and translational data showing these assemblies confer therapeutic benefits in a range of clinically relevant disease contexts, including progressive disease in male mice and in relapsing-remitting disease that mimics the intermittent bouts of disease and remission most MS patients initially experience. Here, the antigen component in the complexes is matched to the disease-causing antigen, resulting in a decrease in paralysis in these models. We show that subcutaneous delivery of assemblies durably prevents diseases and drives tolerance by regulatory remodeling of the draining lymph node. Importantly, we show that subcutaneously delivered assemblies recruit and expand antigen-specific regulatory T cells (TREGS) in draining lymph nodes. Finally, we find a shift of these recruited TREGS from a resting to an activated phenotype. Taken together, these data inform the design of therapeutics for antigen-specific tolerance that could combat autoimmunity by exploiting the role of innate pathways in a disease.

Immunogenicity of intraperitoneal and intranasal liposome adjuvanted VLP vaccines against SARS-CoV-2 infection

Humans get SARS-CoV-2 infection mainly through inhalation; thus, vaccine that induces protective immunity at the virus entry site is important for early control of the infection. In this study, two anionic liposome (L)-adjuvanted VLP vaccines against SARS-CoV-2 were formulated. Baculovirus-Sf21 insect cell system was used for production of VLPs made of full-length S, M and E proteins. S protein of one vaccine (L-SME-VLPs) contained furin cleavage site at the S1/S2 junction, while that of another vaccine (L-S′ME-VLPs) did not. Both vaccines were innocuous and immunogenic when administered IP and IN to mice. Mice immunized IP with L-SME-VLPs/L-S′ME-VLPs (three doses, two-weeks intervals) had serum virus neutralizing (VN) antibodies (in falling order of isotype frequency): IgG3, IgA and IgG2a/IgG3, IgA and IgM, respectively. The L-S′ME VLPs vaccine induced significantly higher serum VN antibody titers than the L-SME-VLPs vaccine. All mice immunized IN with both vaccines had significant rise of VN antibodies in their bronchoalveolar lavage fluids (BALF). The VN antibodies in 67% of immunized mice were Th1- isotypes (IgG2a and/or IgG2b); the immunized mice had also other antibody isotypes in BALF. The intranasal L-S′ME-VLPs should be tested further step-by-step towards the clinical use as effective and safe vaccine against SARS-CoV-2.

IL-36 Gamma: A Novel Adjuvant Cytokine Enhancing Protective Immunity Induced by DNA Immunization with TGIST and TGNSM Against Toxoplasma gondii Infection in Mice

IL-36 Gamma: A Novel Adjuvant Cytokine Enhancing Protective Immunity Induced by DNA Immunization with TGIST and TGNSM Against Toxoplasma gondii Infection in Mice

Microbial education plays a crucial role in harnessing the beneficial properties of microbiota for infectious disease protection in Crassostrea gigas.

The increase in marine diseases, particularly in economically important mollusks, is a growing concern. Among them, the Pacific oyster (Crassostrea gigas) production faces challenges from several diseases, such as the Pacific Oyster Mortality Syndrome (POMS) or vibriosis. The microbial education, which consists of exposing the host immune system to beneficial microorganisms during early life stages is a promising approach against diseases. This study explores the concept of microbial education using controlled and pathogen-free bacterial communities and assesses its protective effects against POMS and Vibrio aestuarianus infections, highlighting potential applications in oyster production. We demonstrate that it is possible to educate the oyster immune system by adding microorganisms during the larval stage. Adding culture based bacterial mixes to larvae protects only against the POMS disease while adding whole microbial communities from oyster donors protects against both POMS and vibriosis. The efficiency of immune protection depends both on oyster origin and on the composition of the bacterial mixes used for exposure. No preferential protection was observed when the oysters were stimulated with their sympatric strains. Furthermore, the added bacteria were not maintained into the oyster microbiota, but this bacterial addition induced long term changes in the microbiota composition and oyster immune gene expression. Our study reveals successful immune system education of oysters by introducing beneficial microorganisms during the larval stage. We improved the long-term resistance of oysters against critical diseases (POMS disease and Vibrio aestuarianus infections) highlighting the potential of microbial education in aquaculture.

The inhibitory effect of Hypericum japonicum on H9N2 avian influenza virus

The H9N2 subtype of avian influenza virus (AIV) causes severe immunosuppression and high mortality in view of its frequent co-infection with other pathogens, resulting in significant economic losses in the poultry industry. Current vaccines provide suboptimal immune protection against H9N2 AIV owing to antigenic variations, highlighting the urgent need for safe and effective antiviral drugs for the prevention and treatment of this virus. This study aimed to investigate the inhibitory effects of Hypericum japonicum extract on H9N2 AIV. Our findings revealed that the extract obtained through resin column separation using 60% ethanol (S06-60%) inhibited H9N2 AIV replication in Madin-Daby canine kidney cells in a dose-dependent manner. The maximum safe concentration of the water-soluble S06-60% extract was determined to be 0.05 mg/mL. Time-course experiments indicated that S06-60% primarily exerted its antiviral effects during the viral pretreatment and adsorption stages. Furthermore, in vivo experiments conducted on specific pathogen-free chickens confirmed the effectiveness of S06-60% in inhibiting H9N2 AIV infection and mitigating associated damage to tracheal and lung tissues. Overall, our study highlights the therapeutic potential of Hypericum japonicum extract S06-60% as a viable antiviral candidate against H9N2 AIV, offering promising implications for its application in poultry health management to reduce the economic impact on the poultry industry.

Age-specific dynamics of neutralizing antibodies, cytokines, and chemokines in response to La Crosse virus infection in mice.

La Crosse virus (LACV) is a primary cause of pediatric arboviral encephalitis in the United States, particularly affecting children aged 16 years or younger. This age-related susceptibility extends to murine models, where weanling mice (3 weeks old) succumb to LACV infection, while adults (≥6 weeks old) demonstrate resistance. Despite its clinical relevance, the host immune response to LACV is not fully understood. In this study, we investigated the roles of neutralizing antibodies (nAbs), cytokines, and chemokines in weanling and adult mice following infection with 5 × 105 plaque-forming units (PFU) of LACV. Weanling mice demonstrated early disease onset with elevated peripheral viremia, but passive transfer of adult serum, confirmed to have nAbs, to naïve weanlings prior to infection completely rescued them from death. Moreover, adult mice had increased Th1 cytokines, Th9/Th17/Th22/Treg cytokines, and many chemokines. In contrast, weanlings had higher Th2 cytokines, correlating with symptoms onset. Flow cytometry and intracellular cytokine staining further demonstrated that weanling mice produced higher levels of IL-4 by CD4+ and CD8+ T cells compared to adults, regardless of infection status. Conversely, LACV-infected adult mice had increased IFN-γ production by CD8+ T cells compared to uninfected controls. Finally, the adoptive transfer of splenocytes from immune adult mice to naïve weanlings delayed neurological symptoms and improved survival. In conclusion, this study links nAbs and cytokine and chemokine responses to protective immunity in adult mice, contrasting with the pathogenesis seen in weanlings. These findings underscore the importance of further research into innate and adaptive immune mechanisms during LACV infection.IMPORTANCELa Crosse virus (LACV) is a primary cause of pediatric encephalitis in the United States, with an impact on children aged 16 years or younger. This age-related susceptibility is recapitulated in mouse models, where young mice succumb to LACV-induced disease, while adults demonstrate resistance. Our understanding of host responses to LACV remains underexplored. This study sheds light on the dynamics of neutralizing antibodies (nAbs), cytokines, and chemokines following LACV infection in both adult and weanling mice. Our study reveals age-specific variations in viremia, neutralizing antibody titers, survivability, and levels of cytokines and chemokines. Adult mice exhibit significantly elevated levels of Th1 cytokines, contrasting with elevated levels of Th2 cytokines observed in weanling mice, often coinciding with the onset of symptoms. These data reveal age-specific dynamics in cytokines and chemokines associated with protective versus pathogenic immunity, emphasizing the need for further studies on innate and adaptive immunity.

VP8 Mosaic Nanoparticles Elicit Cross-Neutralizing Immune Responses and Provide Protection Against Heterotypic Rotavirus Challenge in Mice.

Group A rotaviruses (RVA) remain one of the dominant pathogens causing diarrhea in children under 5 years of age worldwide, despite a sharp decrease of RVA-associated diarrhea and mortality since the introduction of rotavirus vaccines. The decreased effectiveness of live attenuated rotavirus vaccines, coupled with the emergence of new rotavirus genotypes and the risk of cross-species virus transmission, underscores the necessity to develop more effective and broad-spectrum rotavirus vaccines. In this study, we utilized nanoparticles coupled with the SpyCatcher-SpyTag system to effectively display the truncated VP8-1 protein. The modular display of the monovalent VP8-1 proteins markedly increased the immunogenicity of VP8-1. Furthermore, the bivalent display of VP8-1 proteins from simian rotavirus SA11 and lamb rotavirus LLR on the same particle not only increased immunogenicity against homotypic antigens but also elicited robust heterotypic immune responses and conferred effective protection against a distant heterotypic rotavirus with sequence identities of only 62%-66% in an adult mouse model. Therefore, mosaic VP8 nanoparticles could be considered as a viable strategy for the development of the next-generation broad-spectrum rotavirus vaccine.

Protective immune-response of Aeromonas hydrophila phage lysate in crucian carp against direct virulent challenge with A. hydrophila-TPS

Aeromonas hydrophila was a common opportunistic pathogen that was widely found in various aquatic environment and could cause multiple infections in humans and animals. The haemorrhagic septicemia and bacterial enteritis in fish triggered by this pathogen led to significant losses in the aquaculture industry. In this study, we aimed to develop a phage lysate vaccine by lysing the A. hydrophila-TPS strain using phage PZY-Ah, which was previously isolated and preserved in the laboratory. First, we focused on optimizing phage lysis conditions, including different host bacteria culture time, phage lysis time, and phage to bacterial ratios. The optimal conditions were established as follows: culturing the A. hydrophila-TPS strain for 6 h, adding phage at a ratio of 1:10, and mixing for 4 h, which resulted in maximum lysis of the host bacteria. Subsequently, we assessed the immune responses of groups receiving formaldehyde-inactivated vaccines compared to those receiving various concentrations of the phage lysate vaccine. Both the TPS-phage lysate and formaldehyde-inactivated vaccine groups exhibited increased levels of specific immune enzymes (ACP, AKP, LZM, SOD, CAT) and cytokines (IL-1β, TNF-α and IFN-γ) in serum, as well as enhanced humoral immunity (IgM, C3 and C4) in crucian carp. Furthermore, challenge tests conducted post-immunization demonstrated that the high concentration of the TPS strain-lysate vaccine group (1 × 108 CFU/mL) achieved the highest immune protection rate at 88.89 %. Overall, the development of the TPS-phage lysate vaccine significantly enhanced the immunity of crucian carp, providing a higher level of protection and establishing a foundation for the research and development of phage-based aquatic vaccines.

Yellow fever breakthrough infections after yellow fever vaccination: a systematic review and meta-analysis

Yellow fever vaccination is considered to provide effective long-term immunity. However, yellow fever breakthrough infections in vaccinated patients have been reported. In this systematic review and meta-analysis we aimed to identify and summarise all documented symptomatic yellow fever breakthrough infections in the literature occurring less than 10years and 10years or more after primary yellow fever vaccination. We searched MEDLINE (Ovid), Embase (Ovid), and Global Index Medicus for records published between Jan1, 1936 (introduction of yellow fever vaccination) and June 16, 2023. We included prospective and retrospective cohort studies, case series and reports, and epidemiological reports from national and international health organisations reporting symptomatic yellow fever among individuals vaccinated 30days or more before symptom onset. Weexcluded cases vaccinated less than 30days before symptom onset. The primary outcome for the meta-analysis was the proportions of vaccinees among virologically confirmed and probable cases of yellow fever (IgMseroconversion without seroconversion to other flaviviruses). Risk of bias was assessed with an adapted version of the Newcastle-Ottawa Scale. Records of moderate or good quality (probable or confirmed yellow fever diagnosis with documented proof of previous vaccination) were included for random-effects meta-analysis. Thissystematic review and meta-analysis is registered with PROSPERO, number CRD42023450205. After reviewing 1975records, 37records reported a total of 6951yellow fever cases, of which 537were vaccinated. 31records were of low quality. Nine confirmed and 24probable cases with proof of previous yellow fever vaccination were identified, all from Brazil. Confirmed cases were vaccinated 3months to 3years before symptom onset; of these patients two fell severely ill and died. The pooled proportion of verified yellow fever breakthrough infections among probable and confirmed cases was 3% (95% CI 1-19%). No confirmed yellow fever breakthrough infections were identified occurring 10years or more after yellow fever vaccination. Yellow fever breakthrough infections documented in literature are rare, and not necessarily more common 10years or more after primary yellow fever vaccination. This finding suggests that a single dose of yellow fever vaccination is sufficient to provide lifelong protective immunity against symptomatic yellow fever. None.

NK cell membrane/MnO2 hybrid nanoparticle-adjuvanted intranasal vaccines synergistically boost protective immunity against H1N1 influenza infection

Intranasal vaccines hold a huge promise for preventing influenza infection, however, their development is compromised due to mucosal barriers and limited systemic and mucosal immunity. Herein, a novel biomimetic nano-adjuvant based on NK cell membrane (MNK)/MnO2 hybrid nanoparticles (NLipoMn) was developed for intranasal administration of H1N1 inactivated influenza vaccine (IIV). NK cell membrane, served as TLR4 agonist was fused with cationic liposomes encapsulating STING agonist MnO2 NPs (LipoMn) to yield NLipoMn, which inherited versatile characteristics to prolong the nasal retention of IIV. Encouragingly, CCL20 secretion was enhanced by NLipoMn-activated the TLR4/NF-κB pathway in mucosal endothelial cells, thereby promoting submucosal dendritic cells (DCs) recruitment for IIV uptake. Moreover, NLipoMn-IIV synergistically harnessed TLR4 and STING signaling pathway to augment STING activation though NLipoMn-activated the TLR4/NF-κB pathway, which demonstrated a superiority to elicit strong DCs maturation, CD8+ T cells activation, and high levels of antigen-specific IgG, antigen-specific IgA, cytokines secretion, resulting in a robust systemic and mucosal immune responses. Notably, intranasal immunization with NLipoMn-IIV elicited an effective immune protection against homologous and heterologous H1N1 influenza virus infection. This study provides a promising adjuvant candidate to develop needle-free intranasal vaccines that are active against influenza and other respiratory viral infection.

Specific antibody responses to Qβ-displayed Plasmodium falciparum-derived UB05 and MSP3 proteins in mother-neonate couples.

Malaria blood-stage parasite is a critical pathogenic stage responsible for serious adverse outcomes in pregnant women and their neonates. Immunoglobulin G (IgG) antibody responses specific to various asexual blood-stage antigens were well reported in non-pregnant individuals. However, little is still known during placental malaria. To assess the antibody responses specific to Plasmodium falciparum-derived MSP3 and UB05 malaria vaccine candidates in mother-neonate couples, mother's peripheral blood and neonate's cord blood samples were collected at delivery. After malaria diagnostic, plasma levels of IgG and IgG subclass responses specific to UB05, MSP3 and UB05-MSP3 were determined using ELISA. As outcomes, both mothers and neonates had significantly higher IgG responses to UB05 and UB05-MSP3 compared to anti-MSP3 IgG (p < 0.05), irrespective of malaria status. Significant negative correlations were observed between IgG levels specific to the three antigens and parasitaemia (p < 0.01). Anti-UB05 and anti-UB05-MSP3 IgG levels in neonates showed a significant positive correlation with the corresponding mothers' antibodies (rs = 0.25 with p = 0.04; rs = 0.31 with p = 0.01, respectively). UB05MSP3-specific IgG3 and IgG1 subclass responses were significantly higher than the IgG4 subclass (p < 0.01). The neonates IgG1 and IgG3 levels positively correlated with the corresponding antibody subclasses of mothers. These findings suggest an association between UB05 and UB05-MSP3-specific antibody responses and malaria control during pregnancy. Maternal-foetal transfer of MSP3 and UB05-specific IgG occurs during pregnancy, suggesting the interest in the future malaria vaccination strategies in pregnant women to generate early protective immunity in baby against malaria.