Effect of difference doses of Newcastle disease vaccine immunization on growth performance,plasma variables and immune response of broilers

Background： As a member of the Paromyxoviridoe group, Newcastle disease virus （NDV） is the key causative agent of Newcastle disease （ND） that attacks chickens, turkeys and other avian birds. Surviving birds showed lower feed utilization, growth performance or egg production, which results in severe economic losses. The purpose of this study was to determine the effect of different doses of NDV immunization on growth performance, plasma variables and immune response of broiler chickens. Methods： A total of 480 one-day-old Arbor Acres broilers were randomly administrated with 0, 4, 6 or 8 doses of NDV at 12 d and 28 d, respectively. Each group consisted of ten replicates with 12 birds each. Growth performance and organ weight were recorded. Plasma concentration of glucose, total protein, cholesterol, triglycerides and nonesterified fatty acid was determined using commercial kits. The concentration of plasma corticosterone and insulin was measured using commercially available radio immune assay kits. Serum antibody titer and peripheral blood lymphocyte proliferation were also recorded. Results： The results showed that NDV decreased body weight gain （BWG）, and increased Feed：Gain ratio at 1-2 ] d at all doses （P 〈 0.05）. Plasma insulin concentration was lower in all immunization groups after the first immunization at 12 d （P 〈 0.01）. The rest of the plasma indexes were not affected by NDV immunization, including glucose, total protein, cholesterol, triglycerides, nonesterified fatty acid, heterophil/lymphocyte ratio, as well as the proliferation of peripheral blood lymphocyte （P 〉 0.05）. Compared with the control group, NDVtreatment elevated NDV antibody titer at 10 d after the first inoculation （P 〈 0.05）, and at d 5, 9 and 13 after the second inoculation （P 〈 0.05）. Repeated NDV inoculation had no deleterious impacts on body composition at 42 d, and nutrient accretion rates at 8-42 d （P 〉 0.05）. Conclusions： In conclusion, NDV challenge decreased BWG and feed efficiency in earlier stage of growth. However NDV treatment at 6 doses down-regulated the Feed：Gain ratio by 6.36 % throughout the whole growing period. These data suggest that appropriate lower doses of NDV inoculation increase feed efficiency of broiler chickens.

Immune response to inactivated bacterial vector carrying the recombinant K39 antigen of Leishmania infantum in mice

Objective:To evaluate the immunological response elicited by an inactivated bacterial vector carrying the K39 antigen of Leishmania infantum,and a purified antigen.Methods:Mice were subjected to the following treatments:(1)Purified recombinant K39(rK39)protein at a 20μg dose with complete Freund’s adjuvant;(2)Inactivated Escherichia coli(BL21 DE3)carrying the K39 protein at an equivalent total protein content of 200μg;(3)Inactivated bacteria lacking the K39 protein;(4)Non-immunized control animals.Serological monitoring was performed.All groups were challenged by intraperitoneal injection of 10^(7) Leishmania infantum promastigotes.After euthanasia,the liver and spleen were collected to analyze the levels of TNF,IFN-γ,IL-12,IL-4,and IL-10.Results:Mice immunized with purified rK39 or the inactivated bacterial vector carrying the K39 antigen of Leishmania infantum showed a long-lasting immune response with high levels of polyclonal antibodies specifically recognizing the recombinant proteins.The IgG1 subclass was the predominant immunoglobulin;however,the induction of IgG2a and the profile of cytokines produced were indicative of the induction of a mixed-type response.Conclusions:The inactivated bacterial vector carrying the K39 antigen,as well as the purified antigen can induce a long-lasting immune response in immunized mice,predominantly favouring a Th2 profile response.

A new DNA vaccine fused with the C3d-p28 induces a Th2 immune response against amyloid-beta

To enhance anti-amyloid-beta （Aβ） antibody generation and induce a Th2 immune response, we constructed a new DNA vaccine p（Aβ3-10 ）10-C3d-p28.3 encoding ten repeats of Aβ3-10 and three copies of C3d-p28 as a molecular adjuvant. In this study, we administered this adjuvant intramus-cularly to female C57BL/6J mice at 8-10 weeks of age. Enzyme linked immunosorbent assay was used to detect the titer of serum anti-Aβ antibody, isotypes, and cytokines in splenic T cel s. A 3-（4,5-cimethylthiazol-2-yl）-2,5-diphenyl tetrazolium bromide assay was used to detect the prolifera-tion rate of splenic T cel s. Brain sections from a 12-month-old APP/PS1 transgenic mouse were used for detecting the binding capacities of anti-Aβ antibodies to Aβ plaques. The p（Aβ3-10）10-C3d-p28.3 vaccine induced high titers of anti-amyloid-βantibodies, which bound to Aβplaques in APP/PS1 transgenic mouse brain tissue, demonstrating that the vaccine is effective against plaques in a mouse model of Alzheimer’s disease. Moreover, the vaccine elicited a pre-dominantly IgG1 humoral response and low levels of interferon-γ in ex vivo cultured splenocytes, indicating that the vaccine could shift the cel ular immune response towards a Th2 phenotype. This indicated that the vaccine did not elicit a detrimental immune response and had a favorable safety profile. Our results indicate that the p（Aβ3-10）10-C3d-p28.3 vaccine is a promising immunothera-peutic option for Aβvaccination in Alzheimer’s disease.

Visceral leishmaniasis: An immunological viewpoint on asymptomatic infections and post kala azar dermal leishmaniasis

Elimination of visceral leishmaniasis is a priority programme in Indian subcontinent.The World Health Organization has set a new target to eliminate kala-azar by the year 2020 as previous target elimination year(2015) has passed.The elimination programme has successfully curbed the rate of infection in endemic regions; however, there are still few challenges in its route.The current drug control regime is extremely limited and comprises only two(amphotericin B and miltefosine) drugs, which are also susceptible for parasites resistance.Moreover, these drugs do not produce sterile cure, and cured patients may develop post kala-azar dermal leishmaniasis even after a decade of cure leaving behind a potent source of parasitic reservoirs for further disease transmission.A significant proportion of endemic population remain seropositive but aymptomatic for many years without any clinical symptom that serve as latent parasitic reservoirs.The lack of tools to identify live parasites in asymptomatic infections and there association in disease transmission, parameters of sterile cure along with post kala-azar dermal leishmaniasis progression remain a major threat in its elimination.In this review, we discuss the potential of host immune inhibitory mechanisms to identify immune correlates of protective immunity to understand the mystery of asymptomatic infections, sterile cure and post kala azar dermal leishmaniasis.

Regulating Effects of Novel CpG Chitosan-nanoparticles on Immune Responses of Mice to Porcine Paratyphoid Vaccines

Objective To study the regulating effects of a novel CpG oligodeoxynuleotide and the synergistic effect of chitosan-nanoparticles （CNP） with CpG on immune responses of mice, which were used to develop a novel immunoadjuvant to boost immune response to conventional vaccines. Methods A novel CpG ODN containing 11 CpG motifs was synthesized and its bioactivities to stimulate the proliferation of lymphocytes of pig in vitro were detected. Then it was entrapped with CNP prepared in our laboratory by the method of ionic cross linkage, and immunized Kunming mice were co-inoculated with paratyphoid vaccine. The peripheral blood was collected weekly from the tail vein of inoculated mice to detect the contents of IgG, IgA, IgM, and specific antibody against salmonella as well as the levels of interleukin-2 （IL2）, IL-4, and IL-6 by SABC-ELISA assay. The numbers of leucocytes, monocytes, granuloytes, and lymphocytes were calculated separately using the routine method. The experimental mice were orally challenged with virulent salmonella 35 days after inoculation. Results This CpG ODN could remarkably provoke the proliferation of lymphocytes of pig in vitro in contrast with the control （P〈0.05）. Compared with those of the control, immunoglobulins, including IgG, IgA, IgM, and specific antibodies to paratyphoid vaccine, increased significantly in sera from the CpG or CpG-CNP-vaccinated mice （P〈0.05）. IL-2, IL-4, and IL-6 increased remarkably in sera from immunized mice （P〈0.05）. The leucocytes, monocytes, granuloytes, and lymphocytes of the mice immunized with CpG or CpG-CNP were also increased in number （P〈0.05）. After the challenge, these immunity values were elevated in the mice vaccinated with CpG or CpG-CNP. The immunized mice all survived, while the control mice fell ill with evident lesions with diffuse hemorrhage in stomach, small intestine, and peritoneum. Conclusions CpG ODN entrapped with CNP is a promising effective immunoadjuvant for vaccination, which promotes humoral and cellular immune responses, enhances immunity and resistance against salmonella by co-administration with paratyphoid vaccine. Key words：

Induced Th2 dominant immune response in APPswe, PSEN1dE9 transgenic mice after nasal immunization with an adenoviral vector encoding 10 tandem repeats of beta-amyloid 3-10

Immunotherapy for Alzheimer＇s disease （AD） is effective in improving cognitive function in transgenic mouse models of AD. Because the AN1792 [beta-amyloid （Aβ） 1-42] vaccine was halted because of T cell mediated meningoencephalitis, many scientists are searching for a nove） vaccine to avoid the T cell mediated immune response caused by the Aβ1-42. Importantly, the time when the immunization is begun can influence the immune effect. In this study, an adenovirus vaccine was constructed containing 10 x Aβ3-10 repeats and gene adjuvant CpG DNA. Transgenic AD mice were immunized intranasally for 3 months. After 10 × Aβ3-10 vaccine immunization, high titers of anti-Aβ42 IgG1 predominant antibodies were induced. In spatial learning ability and probe tests, the 10 × Aβ3-10 immunized mice showed significantly improved memories compared to control mice. The 10 × Aβ3-10 vaccine resulted in a robust Th2 dominant humoral immune response and reduced learning deficits in AD mice. In addition, the 10 × Aβ3-10 vaccine might be more efficient if administered before Aβ aggregation at an early stage in the AD mouse brain. Thus, the adenovirus vector encoding 10 × Aβ-10 is a promising vaccine for AD.

Co-administration of Interleukin-2 Enhances Cellular and Humoral Immune Responses to HIV Vaccine DNA Prime/MVA Boost Regime

Interleukine-2(IL-2) is a growth factor for antigen-stimulated T lymphocytes and is responsible for ~T-cell clonal expansion after antigen recognition. It has been demonstrated that DNA vaccine-elicited immune responses in mice could be augmented substantially by using either an IL-2 protein or a plasmid expressing ~IL-2. Twenty mice, divided into four experimental groups, were immunized with: (1) sham plasmid; ^(2) HIV-1 DNA vaccine alone; (3) HIV-1 DNA vaccine and IL-2 protein; or (4) HIV-1 DNA vaccine and IL-2 plasmid, separately. All the groups were immunized 3 times at a 2-week interval. Fourteen days after the last DNA vaccine injection, recombinant MVA was injected into all the mice except those in group 1. ELISA and ELISPOT were employed to investigate the effect of IL-2 on DNA vaccine immune responses. The obtained results strongly indicate that the efficacy of HIV vaccine can be enhanced by co-administration of a plasmid encoding IL-2.

Effect of Chicken Akirin2 Gene on Immune Response Induced by VP2 DNA Vaccine of Infectious Bursal Dis-ease Virus

[ Abstracts ] In order to investigate the effect of chicken Akirin2 gene on the immune response induced by VP2 DNA vaccine of infectious bursal disease virus （IBDV）. [ Methods] The 14-day-old SPF chickens were immunized with recombinant plasmids expressing VP2 protein and Akirin2 protein, and strength- ened immunization was conducted at the 14＇~ day after the first immunization. Finally, test chickens were challenged with IBDVBC6-85 virulent strain. [ Resultss ] Test results showed that Akirin2 gene could enhance the specific immune response induced by VP2 DNA vaccine, improve the proliferation of peripheral blood lym- phocytes and ＇affect the expressing of cytokines TNF-a, IFN-Y, IL-1β, IL-2, IL-4, IL 6, IL-9, IL-10, IL-17 and IL-18. Effects of recombinant plasmids co-ex- pressing Akirin2 protein and VP2 protein on cytokine expression showed some differences with the recombinant plasmids expressing Akirir/2 protein or VP2 protein along. [ Conclusions] Chicken Akirin2 gene could significantly enhance the humoral immune response and cellular immune response induced by VP2 DNA vaccine of IBDV.

A review of adjuvants forLeishmania vaccine candidates

Over the last decade, there has been a flurry of research on adjuvants for vaccines, and several novel adjuvants are now licensed products or in late stage clinical development. The success of adjuvants in enhancing the immune response to antigens has led many researchers to re-focus their vaccine development programs. Although several vaccine candidates have been tested against leishmaniasis, there is yet no effective vaccine against this parasitic disease. Recent research has documented that efforts to develop effective Leishmania vaccine have been limited due to lack of an appropriate adjuvant. In view of this, this review paper outlines some of the adjuvants that have been used in Leishmania vaccine candidates and cites a few of the responses obtained from these studies. The aim of the present review is to consolidate these findings to facilitate the application of these adjuvants in general and experimental vaccinology.

Th immune response induced by H pylori vaccine with chitosan as adjuvant and its relation to immune protection

AIM:To study the immunological protective effect of H pylori vaccine with chitosan as an adjuvant and its mechanism.METHODS:Female BALB/c mice were randomly divided into seven groups and orally immunized respectively with PBS,chitosan solution,chitosan particles,H pylori antigen,H pylori antigen plus cholera toxin(CT),H pylori antigen plus chitosan solution,H pylori antigen plus chitosan particles once a week for four weeks.Four weeks after the last immunization,the mice were challenged twice by alive H pylori(1 × 109 CFU/mL)and sacrificed.Part of the gastric mucosa was embedded in paraffin,cut into sections and assayed with Giemsa staining.Part of the gastric mucosa was used to quantitatively culture H pylori.ELISA was used to detect cytokine level in gastric mucosa and anti-H pylori IgG1,IgG2a levels in serum.RESULTS:In the groups with chitosan as an adjuvant,immunological protection was achieved in 60% mice,which was significantly higher than in groups with H pylori antigen alone and without H pylori antigen(P < 0.05 or 0.001).Before challenge,the level of IFN and IL-12 in gastric mucosa was significantly higher in the groups with chitosan as an adjuvant than in the control group and the group without adjuvant(P < 0.05 or 0.005).After challenge,the level of IFN and IL-12 was significantly higher in the groups with adjuvant than in the groups without adjuvant and antigen(P < 0.05 or 0.001).Before challenge,the level of IL-2 in gastric mucosa was not different among different groups.Afterchallenge the level of IL-2 was significantly higher in the groups with adjuvant than in the control group(P < 0.05 or 0.001).Before challenge,the level of IL-10 in gastric mucosa was significantly higher in the groups with chitosan as an adjuvant than in other groups without adjuvant(P < 0.05 or 0.01).After challenge,the level of IL-10 was not different among different groups.Before challenge,the level of IL-4 in gastric mucosa was significantly higher in the groups with chitosan as an adjuvant than in other groups without adjuvant(P < 0.05).After challenge,the level of IL-4 was significantly higher in the groups with chitosan particles as an adjuvant than in the group with CT as an adjuvant(P < 0.05),and in the group with chitosan solution as an adjuvant,the level of IL-4 was significantly higher than that in control group,non-adjuvant group and the groups with CT(P < 0.05 or 0.001).The ratio of anti-H pylori IgG2a/IgG1 in serum was significantly lower in the groups with chitosan as an adjuvant than in the groups with CT as an adjuvant or without adjuvant(P < 0.01).CONCLUSION:H pylori vaccine with chitosan as an adjuvant can protect against H pylori infection and induce both Th1 and Th2 type immune response.

Insights into induction of the immune response by the hepatitis B vaccine

After more than four decades of hepatitis B virus(HBV)vaccine implementation,its safety and efficacy in preventing HBV infection have been proven and several milestones have been achieved.Most countries have included HBV immunization schedules in their health policies and progress has been made regarding universalization of the first HBV vaccine dose at birth.All of these actions have significantly contributed to reducing both the incidence of HBV infection and its related complications.However,there are still many drawbacks to overcome.The main concerns are the deficient coverage rate of the dose at birth and the large adult population that has not been reached timely by universal immunization.Additionally,the current most widely used second-generation vaccines do not induce protective immunity in 5%to 10%of the population,particularly in people over 40-years-old,obese(body mass index>25 kg/m2),heavy smokers,and patients undergoing dialysis or infection with human immunodeficiency virus.Recently developed and approved novel vaccine formulations using more potent adjuvants or multiple antigens have shown better performance,particularly in difficult settings.These advances re-launch the expectations of achieving the World Health Organization’s objective of completing hepatitis control by 2030.

Enhancing cellular immune response to HBV M DNA vaccine in mice by codelivery of interleukin-18 recombinant

Objective:To investigate the effect of interleukin-18 (IL-18) on immune response induced by plasmid encoding hepatitis B virus middle protein antigen and to explore new strategies for prophylactic and therapeutic HBV DNA vaccines.Methods:BALB/c mice were immunized with pCMV-M alone or co-immunized with pcDNA3-18 and pCMV-M and then their sera were collected for analysing anti-HBsAg antibody by ELISA;splenocytes were isolated for detecting specific CTL response and cytokine assay in vitro.Results:The anti-HBs antibody level of mice co-immunized with pcDNA3-18 and pCMV-M was slightly higher than that of mice immunized with pCMV-M alone,but there was not significantly different (P>0.05).Compared with mice injected with pCMV-M, the specific CTL cytotoxity activity of mice immunized with pcDNA3-18 and pCMV-M was significantly enhanced (P<0.05) and the level of IFN-γ in supernatant of splenocytes cultured with HBsAg in vitro was significantly elevated (P<0.05) while the level of IL-4 had no significant difference (P>0.05).Conclusion:The plasmid encoding IL-18 together with HBV M gene DNA vaccines may enhance specific TH1 cells and CTL cellular immune response induced in mice, so that IL-18 is a promising immune adjuvant.

Montanide^TMGel01 ST Adjuvant Enhances PRRS Modified Live Vaccine Efficacy by Regulating Porcine Humoral and Cellular Immune Responses

Porcine reproductive and respiratory syndrome (PRRS) is a devastating disease caused by the PRRS virus. The MontanideTM class of flexible polymeric adjuvants has recently been shown to enhance protective immunity against PRRSV infection in piglets when used in combination with PRRS modified live vaccines (MLV). In this study, we explored the efficacy and immunological mechanisms of protection of MontanideTM Gel01 ST (Gel01) adjuvanted modified live PRRSV vaccine in pigs challenged with two genetically distinct strains of PRRSV. Gel01-MLV reduced lymph node pathology scores in pigs challenged with VR-2332 (parental strain of MLV vaccine) but not that in pigs challenged with MN184A (heterologous strain), when compared to that in pigs vaccinated with un-adjuvanted MLV. Pigs vaccinated with Gel01-MLV had higher levels of PRRS-specific antibodies, as measured by IDEXX ELISA and virus neutralizing antibodies, after vaccination and VR-2332 challenge. In addition, pigs vaccinated with Gel01-MLV had decreased levels of IFN-γ, IL-10, and T-regulatory lymphocytes in the blood as compared to that in pigs vaccinated with MLV alone. Interestingly, we found that addition of Gel01 did not change the profile of other T lymphocyte populations after PRRSV challenge. These results demonstrate that the MLV adjuvanted with Gel01 provides enhanced protection against homologous PRRSV infection, possibly by regulating the production of PRRSV-specific antibodies and cytokines involved in the development of T-regulatory cells. Thus, Gel01 ST is a promising adjuvant that can be formulated with PRRSV MLV vaccines to reduce disease severity and tissue damage caused by PRRSV infection in pigs.

Comparison of Immune Responses against FMD by a DNA Vaccine Encoding the FMDV/O/IRN/2007 VP1 Gene and the Conventional Inactivated Vaccine in an Animal Model

Foot-and-mouth disease virus (FMDV) is highly contagious and responsible for huge outbreaks among cloven hoofed animals. The aim of the present study is to evaluate a plasmid DNA immunization system that expresses the FMDV/O/IRN/2007 VP1 gene and compare it with the conventional inactivated vaccine in an animal model. The VP1 gene was sub-cloned into the unique Kpn I and BamH I cloning sites of the pcDNA3.1+ and pEGFP-N1 vectors to construct the VP1 gene cassettes. The transfected BHKT7 cells with sub-cloned pEGFP-N1-VP1 vector expressed GFP-VP1 fusion protein and displayed more green fluorescence spots than the transfected BHKT7 cells with pEGFP-N1 vector, which solely expressed the GFP protein. Six mice groups were respectively immunized by the sub-cloned pcDNA3.1+-VP1 gene cassette as the DNA vaccine, DNA vaccine and PCMV-SPORT-GMCSF vector (as molecular adjuvant) together, conventional vaccine, PBS (as negative control), pcDNA3.1+ vector (as control group) and PCMV-SPORT vector that contained the GMCSF gene (as control group). Significant neutralizing antibody responses were induced in the mice which were immunized using plasmid vectors expressing the VP1 and GMCSF genes together, the DNA vaccine alone and the conventional inactivated vaccine (P<0.05). Co-administration of DNA vaccine and GMCSF gene improved neutralizing antibody response in comparison with administration of the DNA vaccine alone, but this response was the most for the conventional vaccine group. However, induction of humeral immunity response in the conventional vaccine group was more protective than for the DNA vaccine, but T-cell proliferation and IFN-γ concentration were the most in DNA vaccine with the GMCSF gene. Therefore the group that was vaccinated by DNA vaccine with the GMCSF gene, showed protective neutralizing antibody response and the most Th1 cellular immunity.

Development ofLeishmania vaccines:predicting the future from past and present experience

Leishmaniasis is a disease that ranges in severity infection. Resistance to infection is associated with from skin lesions to serious disfigurement and fatal systemic a T-helper-1 immune response that activates macrophages to kill the intracellular parasite in a nitric oxide-dependent manner. Conversely, disease progression is generally associated with a T-helper-2 response that activates humoral immunity. Current control is based on chemothera- peutic treatments which are expensive, toxic and associated with high relapse and resistance rates. Vaccination remains the best hope for control of all forms of the disease, and the development of a safe, effective and affordable antileishmanial vaccine is a critical global public-health priority. Extensive evidence from studies in animal models indicates that solid protection can be achieved by immunization with defined subunit vaccines or live-at- tenuated strains of Leishmania. However, to date, no vaccine is available despite substantial efforts by many laboratories. Major impediments in Leishmania vaccine development include： lack of adequate funding from national and international agencies, problems related to the translation of data from animal models to human disease, and the transition from the laboratory to the field. Furthermore, a thorough understanding of protective immune responses and generation and maintenance of the immunological memory, an important but least-studied aspect of antiparasitic vaccine development, during Leishmania infection is needed. This review focuses on the progress of the search for an effective vaccine against human and canine leishmaniasis.

Idiotype vaccines for lymphoma:Potential factors predicting the induction of immune responses

Over the last two decades,lymphoma idiotype vaccines have been the first human cancer vaccines to show striking evidence of biological and clinical efficacy on the one hand,as well as clinical benefit on the other.More recently,however,three large-scale,independent,randomized clinical trials on idiotypic vaccination have failed to achieve their main clinical endpoints for reasons likely to depend more on flaws in each clinical trial’s study design than on each vaccination strategy per se.Independently of these considerations,a major hurdle for the development of this substantially innocuous and yet potentially very effective type of treatment has been the fact that,even to date,no factors ascertainable before vaccination have been prospectively singled out as predictors of subsequently vaccine-induced,idiotypespecific immune as well as clinical responses.The aim of this review article is precisely to analyze what has been and what could be done in this respect in order to give a greater chance of success to future trials aimed at regulatory approval of idiotype vaccines.

Humoral immune response to HCV core DNA vaccine in mice

To investigate the humoral immune response induced by HCV core DNA vaccine in mice and to furnish evidence for HCV DNA vaccine for humans. Methods: HCV core DNA vaccine (pcDNA3. 1HCVcore) was constructed by inserting the full-length cDNA of HCV core gene into an eukaryotic expression vector pcDNA3. 1. Balb/c mice were injected intramuscularly with the recombinant construct and serum anti-HCV core antibody was screened by ELISA. Lysate of NIH3T3 cells trans feeted with pcDNA3. 1 core was analyzed by Western-blot and the anti--HCV core antibody positive murine sera were used as specific antibodies to detect the expression of the vaccine. Results: ELISA detection revealed that 3 out of the 10 vaccinated mice produced HCV antibodies. Western-blot analysis showed that the anti--HCV core antibodies could detect HCV core protein expressed by NIH3T3 cells. Conclusion:HCV core DNA vaccine is able to induce specific antibodies in mice.

Leishmania donovani:Immune response and immune evasion with emphasis on PD-1/PDL-1 pathway and role of autophagy

Leishmania donovani is one of the causative agents of visceral leishmaniasis.The immune response against Leishmania depends on CD4^(+)T helper type 1 cells.The immune system is unable to combat Leishmania because the parasite can exert several immune suppressive mechanisms that facilitate escaping the immune responses.One of these mechanisms is the up-regulation of programmed death-1/programmed death ligand-1 pathway which causes T cells to undergo exhaustion.Autophagy is strongly linked to the immune response,with some research indicating that activating autophagy reduces the immune response to some intracellular pathogens,while others indicate that activating autophagy limits the growth of intracellular pathogens.Leishmania was found to subvert the host defense mechanisms for its own persistence,such as Leishmania-induced autophagy modulation.Leishmania was reported to activate autophagy in different studies,thus getting a dual benefit by evading the immune system and simultaneously utilizing the autophagy byproducts as nutrients.In this review,we introduced different immune evasion/suppressive mechanisms used by Leishmania,and different immunotherapies which were developed accordingly.We focused on the programmed death-1/programmed death ligand-1 pathway as well as autophagy with the potential interplay of both mechanisms.

Multi-valent mRNA vaccines against monkeypox enveloped or mature viron surface antigens demonstrate robust immune response and neutralizing activity

Monkeypox was declared a global health emergency by the World Health Organization,and as of March 2023,86,000 confirmed cases and 111 deaths across 110 countries have been reported.Its causal agent,monkeypox virus(MPV)belongs to a large family of double-stranded DNA viruses,Orthopoxviridae,that also includes vaccinia virus(VACV)and others.MPV produces two distinct forms of viral particles during its replication cycles:the enveloped viron(EV)that is released via exocytosis,and the mature viron(MV)that is discharged through lysis of host cells.This study was designed to develop multi-valent m RNA vaccines against monkeypox EV and MV surface proteins,and examine their efficacy and mechanism of action.Four m RNA vaccines were produced with different combinations of surface proteins from EV(A35R and B6R),MV(A29L,E8L,H3L and M1R),or EV and MV,and were administered in Balb/c mice to assess their immunogenicity potentials.A dynamic immune response was observed as soon as seven days after initial immunization,while a strong Ig G response to all immunogens was detected with ELISA after two vaccinations.The higher number of immunogens contributed to a more robust total Ig G response and correlating neutralizing activity against VACV,indicating the additive potential of each immunogen in generating immune response and nullifying VACV infection.Further,the m RNA vaccines elicited an antigen-specific CD4^(+)T cell response that is biased towards Th1.The m RNA vaccines with different combinations of EVand MV surface antigens protected a mouse model from a lethal dose VACV challenge,with the EV and MV antigens-combined vaccine offering the strongest protection.These findings provide insight into the protective mechanism of multi-valent m RNAvaccines against MPV,and also the foundation for further development of effective and safe m RNA vaccines for enhanced protection against monkeypox virus outbreak.

Inactivated SARS-CoV-2 booster vaccine enhanced immune responses in patients with chronic liver diseases

Chronic liver disease(CLD)entails elevated risk of COVID-19 severity and mortality.The effectiveness of the booster dose of inactivated SARS-CoV-2 vaccine in stimulating antibody response in CLD patients is unclear.Therefore,we conducted a cross-sectional study involving 237 adult CLD patients and 170 healthy controls(HC)to analyze neutralizing antibodies(NAbs)against SARS-CoV-2 prototype and BA.4/5 variant,anti-receptor binding domain(RBD)IgG,and total anti-SARS-CoV-2 antibodies.Serum levels of the total anti-SARS-CoV-2 antibodies,anti-RBD IgG and inhibition efficacy of NAbs were significantly elevated in CLD patients after the booster dose compared with the pre-booster dose,but were relatively lower than those of HCs.Induced humoral responses decreased over time after booster vaccination.The neutralization efficiency of the serum against BA.4/5 increased but remained below the inhibition threshold.All four SARS-CoV-2 antibodies,including total anti-SARS-CoV-2 antibodies,anti-RBD IgG and NAbs against prototype and BA.4/5,were lower in patients with severe CLD than those with non-severe CLD.After booster shot,age and time after the last vaccine were the risk factors for seropositivity of NAb against BA.4/5 in CLD patients.Additionally,white blood cell counts and hepatitis B core antibodies were the protective factors,and severe liver disease was the risk factor associated with seropositivity of total anti-SARS-CoV-2 antibodies.Overall,our data uncovered that antibody responses were improved in CLD patients and peaked at 120 days after the booster vaccines.All antibodies excepting total anti-SARS-CoV-2 antibodies declined after peak.CLD patients exhibited impaired immunologic responses to vaccination and weakened NAbs against BA.4/5,which hindered the protective effect of the booster shot against Omicron prevalence.Cellular immune responses should be further evaluated to determine the optimal vaccine regimen for CLD patients.