Vaccines are essential public health tools and play an important role in reducing the burden of infectious diseases in the population.Emerging infectious diseases and outbreaks pose new challenges for vaccine developm...Vaccines are essential public health tools and play an important role in reducing the burden of infectious diseases in the population.Emerging infectious diseases and outbreaks pose new challenges for vaccine development,requiring the rapid design and production of safe and effective vaccines against diseases with limited resources.Here,we focus on the development of vaccines in broad fields ranging from conventional prophylactic vaccines against infectious diseases to therapeutic vaccines against chronic diseases and cancer,providing a comprehensive overview of recent advances in eight different vaccine forms(live attenuated vaccines,inactivated vaccines,polysaccharide and polysaccharide conjugate vaccines,recombinant subunit vaccines,virus-like particle and nanoparticle vaccines,polypeptide vaccines,DNA vaccines,and m RNA vaccines)and the therapeutic vaccines against five solid tumors(lung cancer,breast cancer,colorectal cancer,liver cancer and gastric cancer),three infectious diseases(human immunodeficiency virus,hepatitis B virus and human papillomavirus-induced diseases)and three common chronic diseases(hypertension,diabetes mellitus and dyslipidemia).We aim to provide new insights into vaccine technologies,platforms,applications and understanding of potential next-generation preventive and therapeutic vaccine technologies,paving the way for the vaccines design in the future.展开更多
Varicella-zoster virus(VZV)is a highly infectious agent responsible for both varicella and herpes zoster disease.Despite high efficacy,there remain safety and accessibility concerns with the licensed vaccines.Here,we ...Varicella-zoster virus(VZV)is a highly infectious agent responsible for both varicella and herpes zoster disease.Despite high efficacy,there remain safety and accessibility concerns with the licensed vaccines.Here,we sought to produce a VZV g E immunogen using an E.coli expression system.We found that the soluble expression and yield of g E protein could be enhanced via C-terminal truncations to the protein,thereby facilitating a robust and scalable purification process for the purpose of vaccine manufacturing.The lead truncated g E(aa 31–358),hereafter referred to as tg E,was a homogenous monomer in solution and showed excellent antigenicity.Finally,we assessed and compared the immunogenicity of tg E with commercial v Oka LAV and Shingrix vaccine.We found that aluminum-adjuvanted tg E was immunogenic as compared with v Oka LAV.When adjuvanted with AS01B,a two-dose immunization of tg E showed comparable or better potency in antibody responses and cell-mediated immunity with those of the Shingrix vaccine at the same dosage,especially in terms of the proportion of IFN-γ-expressing CD4^(+)T cells.In conclusion,this method of E.coli-mediate tg E expression offers a cost-effective and scalable strategy to generate an ideal VZV g E immunogen for the development of both varicella and zoster vaccines.展开更多
Dear Editor As of January 2023,coronavirus disease 2019(COVID-19)induced by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused more than 6.7 million deaths,with SARS-CoV-2 variants continuing to alt...Dear Editor As of January 2023,coronavirus disease 2019(COVID-19)induced by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused more than 6.7 million deaths,with SARS-CoV-2 variants continuing to alter the trajectory of the COVID-19 pandemic.Indeed,the prevalence of the newly emergent Omicron sublineages,particularly BA.4/5 and XBB,has highlighted the critical need for the design and production of broadly potent neutralization antibodies to efficiently combat SARS-CoV-2 variants.Neutralizing antibodies(nAbs)XMA01,XMA04,and XMA09,which target noncompeting antigenic sites in RBD(receptor binding domain),exhibit high neutralization potency against earlier disease variants(Supplementary Fig.1a–d),as previously reported by us.展开更多
Epidemiological studies of the COVID-19 patients have suggested the male bias in outcomes of lung illness.To experimentally demonstrate the epidemiological results,we performed animal studies to infect male and female...Epidemiological studies of the COVID-19 patients have suggested the male bias in outcomes of lung illness.To experimentally demonstrate the epidemiological results,we performed animal studies to infect male and female Syrian hamsters with SARS-CoV-2.Remarkably,high viral titer in nasal washings was detectable in male hamsters who presented symptoms of weight loss,weakness,piloerection,hunched back and abdominal respiration,as well as severe pneumonia,pulmonary edema,consolidation,and fibrosis.In contrast with the males,the female hamsters showed much lower shedding viral titers,moderate symptoms,and relatively mild lung pathogenesis.The obvious differences in the susceptibility to SARS-CoV-2 and severity of lung pathogenesis between male and female hamsters provided experimental evidence that SARS-CoV-2 infection and the severity of COVID-19 are associated with gender.展开更多
The pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has resulted in more than 230 million cases and over four million deaths worldwide.Furthermore,multiple emerging SARS-CoV-2 variants ha...The pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has resulted in more than 230 million cases and over four million deaths worldwide.Furthermore,multiple emerging SARS-CoV-2 variants have shown enhanced infectivity,transmissibility,pathogenicity and ability to escape neutralization by vaccine-induced humoral immunity[1].The antibody resistance of SARS-CoV-2 variants constitutes a challenge for current vaccines and therapeutic antibodies.No specific antiviral is currently available for coronavirus in humans[2].Although remdesivir was approved by the FDA for the treatment of SARS-CoV-2 infection,the therapeutic effect is limited,particularly for critical cases with severe pneumonia.展开更多
T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens,thereby engaging with CD3 on the T cell receptor.This linkage between tumor cells and T cells actively triggers T...T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens,thereby engaging with CD3 on the T cell receptor.This linkage between tumor cells and T cells actively triggers T cell activation and initiates targeted killing of the identified tumor cells.These antibodies have emerged as one of the most promising avenues within tumor immunotherapy.However,despite success in treating hematological malignancies,significant advancements in solid tumors have yet to be explored.In this review,we aim to address the critical challenges associated with T cellredirecting bispecific antibodies and explore novel strategies to overcome these obstacles,with the ultimate goal of expanding the application of this therapy to include solid tumors.展开更多
In vaccine development,broadly or cross-type neutralizing antibodies(bnAbs or cnAbs)are frequently targeted to enhance protection.Utilizing immunodominant antibodies could help fine-tune vaccine immunogenicity and aug...In vaccine development,broadly or cross-type neutralizing antibodies(bnAbs or cnAbs)are frequently targeted to enhance protection.Utilizing immunodominant antibodies could help fine-tune vaccine immunogenicity and augment the precision of immunization strategies.However,the methodologies to capitalize on the attributes of bnAbs in vaccine design have not been clearly elucidated.In this study,we discovered a cross-type neutralizing monoclonal antibody,13H5,against human papillomavirus 6(HPV6)and HPV11.This nAb exhibited a marked preference for HPV6,demonstrating superior binding activity to virus-like particles(VLPs)and significantly higher prevalence in anti-HPV6 human serum as compared to HPV11 antiserum(90%vs.31%).Through co-crystal structural analysis of the HPV6 L1 pentamer:13H5 complex,we delineated the epitope as spanning four segments of amino acids(Phe42-Ala47,Gly172-Asp173,Glu255-Val275,and Val337-Tyr351)on the L1 surface loops.Further interaction analysis and site-directed mutagenesis revealed that the Ser341 residue in the HPV6 HI loop plays a critical role in the interaction between 13H5 and L1.Substituting Ser341 with alanine,which is the residue type present in HPV11 L1,almost completely abolished binding activity to 13H5.By swapping amino acids in the HPV11 HI loop with corresponding residues in HPV6 L1(Ser341,Thr338,and Thr339),we engineered chimeric HPV11-6HI VLPs.Remarkably,the chimeric HPV11-6HI VLPs shifted the high immunodominance of 13H5 from HPV6 to the engineered VLPs and yielded comparable neutralization titers for both HPV6 and HPV11 in mice and non-human primates.This approach paves the way for the design of broadly protective vaccines from antibodies within the main immunization reservoir.展开更多
Continual evolution of the severe acute respiratory syndrome coronavirus(SARS-CoV-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or vaccination.Th...Continual evolution of the severe acute respiratory syndrome coronavirus(SARS-CoV-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or vaccination.The rapid nature of these changes has incited a need for the development of superior broad nAbs(bnAbs)and/or the rational design of an antibody cocktail that can protect against the mutated virus strain.Here,we report two angiotensin-converting enzyme 2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants.Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing.Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5.Together,these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.展开更多
Immunotherapy employs the immune system to combat diseases including cancer,autoimmune diseases,infectious diseases and degenerative diseases,for both treatment and prevention of the conditions.The application of immu...Immunotherapy employs the immune system to combat diseases including cancer,autoimmune diseases,infectious diseases and degenerative diseases,for both treatment and prevention of the conditions.The application of immunotherapies has a long history,with the milestone of identifying cow pox as the smallpox vaccine more than 200 years ago as an example(Cook,1996).After that,in 1890,Emil Behring and Kitasato Shibasaburōpublished the first paper on serum therapy which ushered an era of antibody therapy.The progress on basic research of immunological principles and the boost of bioengineering facilitates the fast evolution of immunotherapy in recent years.Immunotherapy has changed the landscape of healthcare and promoted some advanced concepts to control diseases in medicine.In this issue,we selected the major topics on immunotherapy including antibody therapy,vaccine,and immune cell therapy for summarizing current progress in this field.展开更多
Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has infected more than 200 million people,causing coronavirus disease 2019(COVID-19)worldwide.Lungs are the primary target organ of SARS-CoV-2 inf...Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has infected more than 200 million people,causing coronavirus disease 2019(COVID-19)worldwide.Lungs are the primary target organ of SARS-CoV-2 infection.The mild COVID-19 cases develop symptoms of fever,fatigue,muscle weakness,chest pain,headache and cough(Chen et al.,2020;Wang et al.,2020;Zhu et al.,2020),while severe COIVD-19 cases might have pneumonia,breathing difficulties,multiple organ failure and death(Chen et al.,2020;Wang et al.,2020;Zhu et al.,2020).Both the clinicians and researchers have largely focused on the acute phase of COVID-19,but the long-term health consequences of the COVID-19 patients after clinical recovery remain less investigated.Several clinical cohorts demonstrated that some patients discharged from hospital still experience symptoms including fatigue,muscle weakness,chest pain,cough and breathing difficulties(Carfi et al.,2020;Lim et al.,2020;Huang et al.,2021).Moreover,severely impaired pulmonary diffusion capacities and abnormal chest imaging manifestations were observed in some convalescent patients(Huang et al.,2021).Surprisingly,residual virus(An et al.,2020;Yao et al.,2020;Kim et al.,2021)were detected in some convalescent patients.展开更多
基金supported by the National Key Research and Development Program of China(2021YFC2301404)the National Natural Science Foundation of China(81991490,82001756)+2 种基金the Health Education Joint Project of Fujian Province(2019-WJ-05)the President Foundation of Xiamen University(20720200062)CAMS Innovation Fund for Medical Sciences of China(2019RU022)。
文摘Vaccines are essential public health tools and play an important role in reducing the burden of infectious diseases in the population.Emerging infectious diseases and outbreaks pose new challenges for vaccine development,requiring the rapid design and production of safe and effective vaccines against diseases with limited resources.Here,we focus on the development of vaccines in broad fields ranging from conventional prophylactic vaccines against infectious diseases to therapeutic vaccines against chronic diseases and cancer,providing a comprehensive overview of recent advances in eight different vaccine forms(live attenuated vaccines,inactivated vaccines,polysaccharide and polysaccharide conjugate vaccines,recombinant subunit vaccines,virus-like particle and nanoparticle vaccines,polypeptide vaccines,DNA vaccines,and m RNA vaccines)and the therapeutic vaccines against five solid tumors(lung cancer,breast cancer,colorectal cancer,liver cancer and gastric cancer),three infectious diseases(human immunodeficiency virus,hepatitis B virus and human papillomavirus-induced diseases)and three common chronic diseases(hypertension,diabetes mellitus and dyslipidemia).We aim to provide new insights into vaccine technologies,platforms,applications and understanding of potential next-generation preventive and therapeutic vaccine technologies,paving the way for the vaccines design in the future.
基金supported by the National Key Research and Development Program of China(2021YFC2301404)the National Natural Science Foundation of China(81991490)+2 种基金the Industry-University-Academy Cooperation Program of Xiamen(2022CXY0107)the Principal Fund(20720220006 and 20720220004)CAMS Innovation Fund for Medical Sciences(2019RU022)。
文摘Varicella-zoster virus(VZV)is a highly infectious agent responsible for both varicella and herpes zoster disease.Despite high efficacy,there remain safety and accessibility concerns with the licensed vaccines.Here,we sought to produce a VZV g E immunogen using an E.coli expression system.We found that the soluble expression and yield of g E protein could be enhanced via C-terminal truncations to the protein,thereby facilitating a robust and scalable purification process for the purpose of vaccine manufacturing.The lead truncated g E(aa 31–358),hereafter referred to as tg E,was a homogenous monomer in solution and showed excellent antigenicity.Finally,we assessed and compared the immunogenicity of tg E with commercial v Oka LAV and Shingrix vaccine.We found that aluminum-adjuvanted tg E was immunogenic as compared with v Oka LAV.When adjuvanted with AS01B,a two-dose immunization of tg E showed comparable or better potency in antibody responses and cell-mediated immunity with those of the Shingrix vaccine at the same dosage,especially in terms of the proportion of IFN-γ-expressing CD4^(+)T cells.In conclusion,this method of E.coli-mediate tg E expression offers a cost-effective and scalable strategy to generate an ideal VZV g E immunogen for the development of both varicella and zoster vaccines.
基金This work was supported by grants from the National Key Research and Development Program of China(grant no.2022YFC0869900)the National Natural Science Foundation of China(grant nos.81991491,82272305)+2 种基金the Fundamental Research Funds for the Central Universities(grant no.20720220006)China Postdoctoral Science Foundation(grant nos.2022M722659)CAMS Innovation Fund for Medical Sciences(grant no.2019RU022).
文摘Dear Editor As of January 2023,coronavirus disease 2019(COVID-19)induced by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused more than 6.7 million deaths,with SARS-CoV-2 variants continuing to alter the trajectory of the COVID-19 pandemic.Indeed,the prevalence of the newly emergent Omicron sublineages,particularly BA.4/5 and XBB,has highlighted the critical need for the design and production of broadly potent neutralization antibodies to efficiently combat SARS-CoV-2 variants.Neutralizing antibodies(nAbs)XMA01,XMA04,and XMA09,which target noncompeting antigenic sites in RBD(receptor binding domain),exhibit high neutralization potency against earlier disease variants(Supplementary Fig.1a–d),as previously reported by us.
基金This work was supported by grants from the National Science and Technology Major Project of Infectious Diseases(No.2017ZX10304402-002-003)the National Science and Technology Major Projects for Major New Drugs Innovation and Development(No.2018ZX09711003-005-003)+2 种基金the Science and Technology Project of Fujian Province(2020YZ014001)the Science and Technology Project of Xiamen City(3502Z2020YJ01)the CAMS Innovation Fund for Medical Sciences(No.2019RU022).
文摘Epidemiological studies of the COVID-19 patients have suggested the male bias in outcomes of lung illness.To experimentally demonstrate the epidemiological results,we performed animal studies to infect male and female Syrian hamsters with SARS-CoV-2.Remarkably,high viral titer in nasal washings was detectable in male hamsters who presented symptoms of weight loss,weakness,piloerection,hunched back and abdominal respiration,as well as severe pneumonia,pulmonary edema,consolidation,and fibrosis.In contrast with the males,the female hamsters showed much lower shedding viral titers,moderate symptoms,and relatively mild lung pathogenesis.The obvious differences in the susceptibility to SARS-CoV-2 and severity of lung pathogenesis between male and female hamsters provided experimental evidence that SARS-CoV-2 infection and the severity of COVID-19 are associated with gender.
基金supported by grants from the National Science Key Research and Development Project(No.2020YFC0842600)National Natural Science Foundation of China(No.82002139)+1 种基金China Postdoctoral Science Foundation(No.2020T130362,No.2020M682092)the CAMS Innovation Fund for Medical Sciences(No.2019RU022).
文摘The pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has resulted in more than 230 million cases and over four million deaths worldwide.Furthermore,multiple emerging SARS-CoV-2 variants have shown enhanced infectivity,transmissibility,pathogenicity and ability to escape neutralization by vaccine-induced humoral immunity[1].The antibody resistance of SARS-CoV-2 variants constitutes a challenge for current vaccines and therapeutic antibodies.No specific antiviral is currently available for coronavirus in humans[2].Although remdesivir was approved by the FDA for the treatment of SARS-CoV-2 infection,the therapeutic effect is limited,particularly for critical cases with severe pneumonia.
基金supported by the National Natural Science Foundation of China(Nos.32070940 and 81991491)the China Postdoctoral Science Foundation(No.2021M700115)+2 种基金the Postdoctoral Innovation Talents Support Program(No.BX20220189,China)the Science and Technology Planning Project of Fujian Province(No.2022L3080,China)the CAMS Innovation Fund for Medical Sciences(No.2019RU022,China).
文摘T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens,thereby engaging with CD3 on the T cell receptor.This linkage between tumor cells and T cells actively triggers T cell activation and initiates targeted killing of the identified tumor cells.These antibodies have emerged as one of the most promising avenues within tumor immunotherapy.However,despite success in treating hematological malignancies,significant advancements in solid tumors have yet to be explored.In this review,we aim to address the critical challenges associated with T cellredirecting bispecific antibodies and explore novel strategies to overcome these obstacles,with the ultimate goal of expanding the application of this therapy to include solid tumors.
基金supported by the National Key Research and Development Program of China(2021YFC2301404)the National Natural Science Foundation of China(82271873)+3 种基金the CAMS Innovation Fund for Medical Sciences(2019RU022)the Xiamen Industry-University-Research Project(2022CXY0107)the Natural Science Foundation of Xiamen City(3502Z20227165)the Fundamental Research Funds for the Central Universities(20720220006 and 20720220004).
文摘In vaccine development,broadly or cross-type neutralizing antibodies(bnAbs or cnAbs)are frequently targeted to enhance protection.Utilizing immunodominant antibodies could help fine-tune vaccine immunogenicity and augment the precision of immunization strategies.However,the methodologies to capitalize on the attributes of bnAbs in vaccine design have not been clearly elucidated.In this study,we discovered a cross-type neutralizing monoclonal antibody,13H5,against human papillomavirus 6(HPV6)and HPV11.This nAb exhibited a marked preference for HPV6,demonstrating superior binding activity to virus-like particles(VLPs)and significantly higher prevalence in anti-HPV6 human serum as compared to HPV11 antiserum(90%vs.31%).Through co-crystal structural analysis of the HPV6 L1 pentamer:13H5 complex,we delineated the epitope as spanning four segments of amino acids(Phe42-Ala47,Gly172-Asp173,Glu255-Val275,and Val337-Tyr351)on the L1 surface loops.Further interaction analysis and site-directed mutagenesis revealed that the Ser341 residue in the HPV6 HI loop plays a critical role in the interaction between 13H5 and L1.Substituting Ser341 with alanine,which is the residue type present in HPV11 L1,almost completely abolished binding activity to 13H5.By swapping amino acids in the HPV11 HI loop with corresponding residues in HPV6 L1(Ser341,Thr338,and Thr339),we engineered chimeric HPV11-6HI VLPs.Remarkably,the chimeric HPV11-6HI VLPs shifted the high immunodominance of 13H5 from HPV6 to the engineered VLPs and yielded comparable neutralization titers for both HPV6 and HPV11 in mice and non-human primates.This approach paves the way for the design of broadly protective vaccines from antibodies within the main immunization reservoir.
基金supported by grants from the National Key Research and Development Program of China (No.2021YFC2301404)the National Natural Science Foundation of China (Nos.81991491,82272305,and 32170942)+4 种基金Fujian Natural Science Foundation (No.2020J06007)the Industry-University-Research Project of Xiamen (No.2022CXY0106)the Fundamental Research Funds for the Central Universities (Nos.20720220006 and 20720220004)National Postdoctoral Science Foundation of China (No.2021M712659)CAMS Innovation Fund for Medical Sciences (No.2019RU022).
文摘Continual evolution of the severe acute respiratory syndrome coronavirus(SARS-CoV-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or vaccination.The rapid nature of these changes has incited a need for the development of superior broad nAbs(bnAbs)and/or the rational design of an antibody cocktail that can protect against the mutated virus strain.Here,we report two angiotensin-converting enzyme 2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants.Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing.Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5.Together,these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.
文摘Immunotherapy employs the immune system to combat diseases including cancer,autoimmune diseases,infectious diseases and degenerative diseases,for both treatment and prevention of the conditions.The application of immunotherapies has a long history,with the milestone of identifying cow pox as the smallpox vaccine more than 200 years ago as an example(Cook,1996).After that,in 1890,Emil Behring and Kitasato Shibasaburōpublished the first paper on serum therapy which ushered an era of antibody therapy.The progress on basic research of immunological principles and the boost of bioengineering facilitates the fast evolution of immunotherapy in recent years.Immunotherapy has changed the landscape of healthcare and promoted some advanced concepts to control diseases in medicine.In this issue,we selected the major topics on immunotherapy including antibody therapy,vaccine,and immune cell therapy for summarizing current progress in this field.
文摘Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has infected more than 200 million people,causing coronavirus disease 2019(COVID-19)worldwide.Lungs are the primary target organ of SARS-CoV-2 infection.The mild COVID-19 cases develop symptoms of fever,fatigue,muscle weakness,chest pain,headache and cough(Chen et al.,2020;Wang et al.,2020;Zhu et al.,2020),while severe COIVD-19 cases might have pneumonia,breathing difficulties,multiple organ failure and death(Chen et al.,2020;Wang et al.,2020;Zhu et al.,2020).Both the clinicians and researchers have largely focused on the acute phase of COVID-19,but the long-term health consequences of the COVID-19 patients after clinical recovery remain less investigated.Several clinical cohorts demonstrated that some patients discharged from hospital still experience symptoms including fatigue,muscle weakness,chest pain,cough and breathing difficulties(Carfi et al.,2020;Lim et al.,2020;Huang et al.,2021).Moreover,severely impaired pulmonary diffusion capacities and abnormal chest imaging manifestations were observed in some convalescent patients(Huang et al.,2021).Surprisingly,residual virus(An et al.,2020;Yao et al.,2020;Kim et al.,2021)were detected in some convalescent patients.