Rapid Induction of Long-Lasting Systemic and Mucosal Immunity via Thermostable Microneedle-Mediated Chitosan Oligosaccharide-Encapsulated DNA Nanoparticles
通过恒温微针诱导壳聚糖寡糖包被 DNA 纳米粒子快速诱导持久的全身和黏膜免疫力

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This article references 46 other publications.

1. 1

   Eyawo, O.; Viens, A. M.; Ugoji, U. C. Lockdowns and low- and middle-income countries: building a feasible, effective, and ethical COVID-19 response strategy. Global Health 2021, 17 (1), 13  DOI: 10.1186/s12992-021-00662-y

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   1

   Lockdowns and low- and middle-income countries: building a feasible, effective, and ethical COVID-19 response strategy

   Eyawo Oghenowede; Viens A M; Ugoji Uchechukwu Chidiebere

   Globalization and health (2021), 17 (1), 13 ISSN:.

   Lockdowns can be an effective pandemic response strategy that can buy much needed time to slow disease transmission and adequately scale up preventative, diagnostic, and treatment capacities. However, the broad restrictive measures typically associated with lockdowns, though effective, also comes at a cost - imposing significant social and economic burdens on individuals and societies, especially for those in low- and middle-income countries (LMICs). Like most high-income countries (HICs), many LMICs initially adopted broad lockdown strategies for COVID-19 in the first wave of the pandemic. While many HICs experiencing subsequent waves have returned to employing lockdown strategies until they can receive the first shipments of COVID-19 vaccine, many LMICs will likely have to wait much longer to get comparable access for their own citizens. In leaving LMICs vulnerable to subsequent waves for a longer period of time without vaccines, there is a risk LMICs will be tempted to re-impose lockdown measures in the meantime. In response to the urgent need for more policy development around the contextual challenges involved in employing such measures, we propose some strategies LMICs could adopt for safe and responsible lockdown entrance/exit or to avoid re-imposing coercive restrictive lockdown measures altogether.

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2. 2

   Feng, F.; Wen, Z.; Chen, J.; Yuan, Y.; Wang, C.; Sun, C. Strategies to Develop a Mucosa-Targeting Vaccine against Emerging Infectious Diseases. Viruses 2022, 14 (3), 520,  DOI: 10.3390/v14030520

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   2

   Strategies to Develop a Mucosa-Targeting Vaccine against Emerging Infectious Diseases

   Feng, Fengling; Wen, Ziyu; Chen, Jiaoshan; Yuan, Yue; Wang, Congcong; Sun, Caijun

   Viruses (2022), 14 (3), 520CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)

   A review. Numerous pathogenic microbes, including viruses, bacteria, and fungi, usually infect the host through the mucosal surfaces of the respiratory tract, gastrointestinal tract, and reproductive tract. The mucosa is well known to provide the first line of host defense against pathogen entry by phys., chem., biol., and immunol. barriers, and therefore, mucosa-targeting vaccination is emerging as a promising strategy for conferring superior protection. However, there are still many challenges to be solved to develop an effective mucosal vaccine, such as poor adhesion to the mucosal surface, insufficient uptake to break through the mucus, and the difficulty in avoiding strong degrdn. through the gastrointestinal tract. Recently, increasing efforts to overcome these issues have been made, and we herein summarize the latest findings on these strategies to develop mucosa-targeting vaccines, including a novel needle-free mucosa-targeting route, the development of mucosa-targeting vectors, the administration of mucosal adjuvants, encapsulating vaccines into nanoparticle formulations, and antigen design to conjugate with mucosa-targeting ligands. Our work will highlight the importance of further developing mucosal vaccine technol. to combat the frequent outbreaks of infectious diseases.

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3. 3

   Seaman, C. P.; Kahn, A. L.; Kristensen, D.; Steinglass, R.; Spasenoska, D.; Scott, N.; Morgan, C. Controlled temperature chain for vaccination in low- and middle-income countries: a realist evidence synthesis. Bull. World Health Organ. 2022, 100 (8), 491– 502,  DOI: 10.2471/BLT.21.287696

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   3

   Controlled temperature chain for vaccination in low- and middle-income countries: a realist evidence synthesis

   Seaman Christopher P; Scott Nick; Kahn Anna-Lea; Kristensen Debra; Steinglass Robert; Spasenoska Dijana; Morgan Christopher

   Bulletin of the World Health Organization (2022), 100 (8), 491-502 ISSN:.

   Objective: To evaluate the evidence describing how the controlled temperature chain approach for vaccination could lead to improved equitable immunization coverage in low- and middle-income countries. Methods: We created a theory of change construct from the Controlled temperature chain: strategic roadmap for priority vaccines 2017-2020, containing four domains: (i) uptake and demand for the approach; (ii) compliance and safe use of the approach; (iii) programmatic efficiency gains from the approach; and (iv) improved equitable immunization coverage. To verify and improve the theory of change, we applied a realist review method to analyse published descriptions of controlled temperature chain or closely related experiences. Findings: We evaluated 34 articles, describing 22 unique controlled temperature chain or closely related experiences across four World Health Organization regions. We identified a strong demand for this approach among service delivery providers; however, generating an equal level of demand among policy-makers requires greater evidence on economic benefits and on vaccination coverage gains, and use case definitions. Consistent evidence supported safety of the approach when integrated into special vaccination programmes. Feasible training and supervision supported providers in complying with protocols. Time-savings were the main evidence for efficiency gains, while cost-saving data were minimal. Improved equitable coverage was reported where vaccine storage beyond the cold chain enabled access to hard-to-reach populations. No evidence indicated an inferior vaccine effectiveness nor increased adverse event rates for vaccines delivered under the approach. Conclusion: Synthesized evidence broadly supported the initial theory of change. Addressing evidence gaps on economic benefits and coverage gains may increase future uptake.

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4. 4

   Freeman, D.; Lambe, S.; Yu, L. M.; Freeman, J.; Chadwick, A.; Vaccari, C.; Waite, F.; Rosebrock, L.; Petit, A.; Vanderslott, S.; Lewandowsky, S.; Larkin, M.; Innocenti, S.; McShane, H.; Pollard, A. J.; Loe, B. S. Injection fears and COVID-19 vaccine hesitancy. Psychol. Med. 2023, 53 (4), 1185– 1195,  DOI: 10.1017/S0033291721002609

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   Injection fears and COVID-19 vaccine hesitancy

   Freeman Daniel; Lambe Sinead; Freeman Jason; Waite Felicity; Rosebrock Laina; Petit Ariane; Freeman Daniel; Lambe Sinead; Waite Felicity; Rosebrock Laina; Petit Ariane; Freeman Daniel; Waite Felicity; Yu Ly-Mee; Chadwick Andrew; Vaccari Cristian; Vanderslott Samantha; Pollard Andrew J; Lewandowsky Stephan; Larkin Michael; Innocenti Stefania; McShane Helen; McShane Helen; Pollard Andrew J; Loe Bao Sheng

   Psychological medicine (2023), 53 (4), 1185-1195 ISSN:.

   BACKGROUND: When vaccination depends on injection, it is plausible that the blood-injection-injury cluster of fears may contribute to hesitancy. Our primary aim was to estimate in the UK adult population the proportion of COVID-19 vaccine hesitancy explained by blood-injection-injury fears. METHODS: In total, 15 014 UK adults, quota sampled to match the population for age, gender, ethnicity, income and region, took part (19 January-5 February 2021) in a non-probability online survey. The Oxford COVID-19 Vaccine Hesitancy Scale assessed intent to be vaccinated. Two scales (Specific Phobia Scale-blood-injection-injury phobia and Medical Fear Survey-injections and blood subscale) assessed blood-injection-injury fears. Four items from these scales were used to create a factor score specifically for injection fears. RESULTS: In total, 3927 (26.2%) screened positive for blood-injection-injury phobia. Individuals screening positive (22.0%) were more likely to report COVID-19 vaccine hesitancy compared to individuals screening negative (11.5%), odds ratio = 2.18, 95% confidence interval (CI) 1.97-2.40, p < 0.001. The population attributable fraction (PAF) indicated that if blood-injection-injury phobia were absent then this may prevent 11.5% of all instances of vaccine hesitancy, AF = 0.11; 95% CI 0.09-0.14, p < 0.001. COVID-19 vaccine hesitancy was associated with higher scores on the Specific Phobia Scale, r = 0.22, p < 0.001, Medical Fear Survey, r = 0.23, p = <0.001 and injection fears, r = 0.25, p < 0.001. Injection fears were higher in youth and in Black and Asian ethnic groups, and explained a small degree of why vaccine hesitancy is higher in these groups. CONCLUSIONS: Across the adult population, blood-injection-injury fears may explain approximately 10% of cases of COVID-19 vaccine hesitancy. Addressing such fears will likely improve the effectiveness of vaccination programmes.

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5. 5

   Wang, H.; Cui, M.; Li, S.; Wu, F.; Jiang, S.; Chen, H.; Yuan, J.; Sun, C. Perception and willingness toward various immunization routes for COVID-19 vaccines: a cross-sectional survey in China. Front. Public Health 2023, 11, 1192709,  DOI: 10.3389/fpubh.2023.1192709

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   Perception and willingness toward various immunization routes for COVID-19 vaccines: a cross-sectional survey in China

   Wang Haohang; Cui Mingting; Li Shunran; Wu Fan; Sun Caijun; Jiang Shiqiang; Yuan Jianhui; Chen Hongbiao; Sun Caijun; Sun Caijun

   Frontiers in public health (2023), 11 (), 1192709 ISSN:.

   Background: To date, most vaccines, including the COVID-19 vaccine, are mainly administered by intramuscular injection, which might lead to vaccine hesitancy in some populations due to needle fear. Alternatively, needle-free immunization technology is extensively developed to improve the efficacy and acceptance of vaccination. However, there is no study to report the perception and willingness toward various immunization routes of the COVID-19 vaccine in the general population. Methods: A cross-sectional survey was conducted nationwide using an online questionnaire. Bivariate analyses were undertaken to assess variable associations among the participants who reported a hesitancy to receive the COVID-19 booster vaccination. Multivariable logistic regression with a backward step-wise approach was used to analyze the predicted factors associated with the willingness to receive the COVID-19 booster vaccination. Results: A total of 3,244 valid respondents were included in this survey, and 63.2% of participants thought they had a good understanding of intramuscular injection, but only 20.7, 9.2, 9.4, and 6.0% of participants had a self-perceived good understanding of inhalation vaccine, nasal spray vaccine, oral vaccine, and microneedle patch vaccine. Correspondingly, there was high acceptance for intramuscular injection (76.5%), followed by oral inhalation (64.4%) and nasal spray (43.0%). Those participants who were only willing to receive an intramuscular vaccine had less vaccine knowledge (OR = 0.78; 95% CI: 0.65-0.94) than those who were willing to receive a needle-free vaccine (OR = 1.97; 95% CI: 1.52-2.57). Some factors were found to be associated with vaccine hesitancy toward booster COVID-19 vaccination. Conclusion: Needle-free vaccination is a promising technology for the next generation of vaccines, but we found that intramuscular injection was still the most acceptable immunization route in this survey. One major reason might be that most people lack knowledge about needle-free vaccination. We should strengthen the publicity of needle-free vaccination technology, and thus improve the acceptance and coverage of vaccination in different populations.

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6. 6

   Yang, Y.; Li, Z.; Huang, P.; Lin, J.; Li, J.; Shi, K.; Lin, J.; Hu, J.; Zhao, Z.; Yu, Y.; Chen, H.; Zeng, X.; Mei, L. Rapidly separating dissolving microneedles with sustained-release colchicine and stabilized uricase for simplified long-term gout management. Acta Pharm. Sin. B 2023, 13 (8), 3454– 3470,  DOI: 10.1016/j.apsb.2023.02.011

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   Rapidly separating dissolving microneedles with sustained-release colchicine and stabilized uricase for simplified long-term gout management

   Yang, Yao; Li, Zimu; Huang, Ping; Lin, Jiachan; Li, Jinyuan; Shi, Kexin; Lin, Jiahui; Hu, Jingwen; Zhao, Zhuoxian; Yu, Yongkang; Chen, Hongzhong; Zeng, Xiaowei; Mei, Lin

   Acta Pharmaceutica Sinica B (2023), 13 (8), 3454-3470CODEN: APSBCW; ISSN:2211-3835. (Elsevier B.V.)

   Despite growing prevalence and incidence, the management of gout remains suboptimal. The intermittent nature of the gout makes the long-term urate-lowering therapy (ULT) particularly important for gout management. However, patients are reluctant to take medication day after day to manage incurable occasional gout flares, and suffer from possible long-term toxicity. Therefore, a safe and easy-to-operate drug delivery system with simple prepn. for the long-term management of gout is very necessary. Here, a chitosan-contg. sustained-release microneedle system co-loaded with colchicine and uricase liposomes were fabricated to achieve this goal. This microneedle system was confirmed to successfully deliver the drug to the skin and maintain a one-week drug retention. Furthermore, its powerful therapeutic potency to manage gout was investigated in both acute gouty and chronic gouty models. Besides, the drug co-delivery system could help avoid long-term daily oral colchicine, a drug with a narrow therapeutic index. This system also avoids mass injection of uricase by improving its stability, enhancing the clin. application value of uricase. In general, this two-drug system reduces the dosage of uricase and colchicine and improves the patient's compliance, which has a strong clin. translation.

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7. 7

   Yang, L.; Yang, Y.; Chen, H.; Mei, L.; Zeng, X. Polymeric microneedle-mediated sustained release systems: Design strategies and promising applications for drug delivery. Asian J. Pharm. Sci. 2022, 17 (1), 70– 86,  DOI: 10.1016/j.ajps.2021.07.002

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   Polymeric microneedle-mediated sustained release systems: Design strategies and promising applications for drug delivery

   Yang Li; Yang Yao; Chen Hongzhong; Mei Lin; Zeng Xiaowei; Mei Lin

   Asian journal of pharmaceutical sciences (2022), 17 (1), 70-86 ISSN:.

   Parenteral sustained release drug formulations, acting as preferable platforms for long-term exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimally invasive and self-administration. Recently, polymeric microneedle-mediated sustained release systems (MN@SRS) have opened up a new way for treatment of many diseases. Here, we reviewed the recent researches in MN@SRS for transdermal delivery, and summed up its typical design strategies and applications in various diseases therapy, particularly focusing on the applications in contraception, infection, cancer, diabetes, and subcutaneous disease. An overview of the present clinical translation difficulties and future outlook of MN@SRS was also provided.

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8. 8

   Menon, I.; Bagwe, P.; Gomes, K. B.; Bajaj, L.; Gala, R.; Uddin, M. N.; D’Souza, M. J.; Zughaier, S. M. Microneedles: A New Generation Vaccine Delivery System. Micromachines 2021, 12 (4), 435,  DOI: 10.3390/mi12040435

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   There is no corresponding record for this reference.
9. 9

   Larraneta, E.; Lutton, R. E. M.; Woolfson, A. D.; Donnelly, R. F. Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development. Mater. Sci. Eng. R-Reports 2016, 104, 1– 32,  DOI: 10.1016/j.mser.2016.03.001

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10. 10

    Iwata, H.; Kakita, K.; Imafuku, K.; Takashima, S.; Haga, N.; Yamaguchi, Y.; Taguchi, K.; Oyamada, T. Safety and dose-sparing effect of Japanese encephalitis vaccine administered by microneedle patch in uninfected, healthy adults (MNA-J): a randomised, partly blinded, active-controlled, phase 1 trial. Lancet Microbe 2022, 3 (2), E96– E104,  DOI: 10.1016/S2666-5247(21)00269-X

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    10

    Safety and dose-sparing effect of Japanese encephalitis vaccine administered by microneedle patch in uninfected, healthy adults (MNA-J): a randomised, partly blinded, active-controlled, phase 1 trial

    Iwata, Hiroaki; Kakita, Kosuke; Imafuku, Keisuke; Takashima, Shota; Haga, Naoya; Yamaguchi, Yasuyuki; Taguchi, Kenji; Oyamada, Takayoshi

    Lancet Microbe (2022), 3 (2), e96-e104CODEN: LMAIAR; ISSN:2666-5247. (Elsevier Ltd.)

    Background It is unclear whether microneedle vaccinations of Japanese encephalitis virus can induce sufficient neutralising antibodies and reduce the amt. of vaccine needed. We aimed to assess the safety and dose-sparing effect of a microneedle vaccine patch against Japanese encephalitis in healthy individuals who are naive to both the vaccine and natural infection. Methods The MNA-J study was a randomised, partly blinded, active-controlled, phase 1 clin. trial at Hokkaido University (Sapporo, Japan) that enrolled healthy adults aged 20-34 years with no history of Japanese encephalitis vaccination nor of infection as confirmed by seronegativity. We excluded individuals who had been infected with or vaccinated against Japanese encephalitis. Eligible participants were randomly assigned (1:1:1) to one of three groups to receive inactivated Japanese encephalitis vaccine administered twice, 3 wk apart, by either 2·5 μg per injection by s.c. injection, 0·63 μg per patch by high-dose microneedle array (MNA-25%), or 0·25 μg per patch by low-dose microneedle array (MNA-10%). The randomisation sequence, using stratification by cohort and blocks of six, was computer-generated by a statistician who was unaware of group assignment. After administration, the remaining amt. of unadministered vaccine was measured by ELISA and calcd. as the delivered amt. of vaccine. The primary outcome was the neutralising antibody titer at day 42 after first immunization. Successful seroconversion was defined as post-vaccination titers of 1·3 (log10) or higher in individuals whose pre-vaccination titers had been less than 1 (log10). Findings Between Aug 31 and Sept 2, 2019, 39 participants were enrolled and each was randomly assigned to a group (n = 13 per group). No serious adverse events were obsd. All participants in the microneedle array groups had a localised erythematous reaction. The amt. of vaccine delivered by microneedle array to each participant was 0·63-1·15 μg (50-92%) of the full 1·26 μg for the MNA-25% group and 0·25-0·41 μg (51-84%) of the full 0·50 μg for the MNA-10% group. All participants demonstrated seroconversion at day 42, and the mean titers (log10) were 2·55 for MNA-25%, 2·04 for MNA-10%, and 2·08 for s.c. injection. Interpretation A microneedle patch of the Japanese encephalitis vaccine is safe, well tolerated, and immunogenically effective. The dose-sparing effect suggests a significant potential to reduce the amt. of immunogens needed. However, improved delivery is needed to make it more tolerable and user friendly.

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11. 11

    Vander Straeten, A.; Sarmadi, M.; Daristotle, J. L.; Kanelli, M.; Tostanoski, L. H.; Collins, J.; Pardeshi, A.; Han, J.; Varshney, D.; Eshaghi, B.; Garcia, J.; Forster, T. A.; Li, G.; Menon, N.; Pyon, S. L.; Zhang, L.; Jacob-Dolan, C.; Powers, O. C.; Hall, K.; Alsaiari, S. K.; Wolf, M.; Tibbitt, M. W.; Farra, R.; Barouch, D. H.; Langer, R.; Jaklenec, A. A microneedle vaccine printer for thermostable COVID-19 mRNA vaccines. Nat. Biotechnol. 2023,  DOI: 10.1038/s41587-023-01774-z

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    There is no corresponding record for this reference.
12. 12

    Feng, F.; Hao, H.; Zhao, J.; Li, Y.; Zhang, Y.; Li, R.; Wen, Z.; Wu, C.; Li, M.; Li, P.; Chen, L.; Tang, R.; Wang, X.; Sun, C. Shell-mediated phagocytosis to reshape viral-vectored vaccine-induced immunity. Biomaterials 2021, 276, 121062  DOI: 10.1016/j.biomaterials.2021.121062

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    12

    Shell-mediated phagocytosis to reshape viral-vectored vaccine-induced immunity

    Feng, Fengling; Hao, Haibin; Zhao, Jin; Li, Yanjun; Zhang, Ying; Li, Ruiting; Wen, Ziyu; Wu, Chunxiu; Li, Minchao; Li, Pingchao; Chen, Ling; Tang, Ruikang; Wang, Xiaoyu; Sun, Caijun

    Biomaterials (2021), 276 (), 121062CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

    Adenovirus (Ad) has been extensively developed as a gene delivery vector, but the potential side effect caused by systematic immunization remains one major obstacle for its clin. application. Needle-free mucosal immunization with Ad-based vaccine shows advantages but still faces poor mucosal responses. We herein report that the chem. engineering of single live viral-based vaccine effectively modulated the location and pattern of the subsequently elicited immunity. Through precisely assembly of functional materials onto single live Ad particle, the modified virus entered host cell in a phagocytosis-dependent manner, which is completely distinct from the receptor-mediated entry of native Ad. RNA-Seq data further demonstrated that the modified Ad-induced innate immunity was sharply reshaped via phagocytosis-related pathway, therefore promoting the activation and mature of antigen presentation cells (APC). Moreover, the functional shell enabled the modified Ad-based vector with enhanced muco-adhesion to nasal tissues in mice, and then prolonged resident time onto mucosal surface, leading to the robust mucosal IgA prodn. and T cell immunity at local and even remote mucosal-assocd. lymphoid tissues. This study demonstrated that vaccine-induced immunity can be well modulated by chem. engineering, and this method provides the rational design for needle-free mucosa-targeting vaccine against a variety of emerging infectious diseases.

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13. 13

    Sun, C. J.; Pan, S. P.; Xie, Q. X.; Xiao, L. J. Preparation of chitosan-plasmid DNA nanoparticles encoding zona pellucida glycoprotein-3alpha and its expression in mouse. Mol. Reprod. Dev. 2004, 68 (2), 182– 8,  DOI: 10.1002/mrd.20058

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    13

    Preparation of chitosan-plasmid DNA nanoparticles encoding zona pellucida glycoprotein-3α and its expression in mouse

    Sun, Cai-Jun; Pan, Shan-Pei; Xie, Qi-Xuan; Xiao, Luan-Juan

    Molecular Reproduction and Development (2004), 68 (2), 182-188CODEN: MREDEE; ISSN:1040-452X. (Wiley-Liss, Inc.)

    In the present study, the porcine zona pellucida (ZP)-3α eukaryotic expression vector pVAX1-pZP3α was constructed by genetic recombinant technol., then the recombinant plasmid was encapsulated in nanoparticles with chitosan, and the imaging of chitosan/pVAX1-pZP3α nanoparticles by At. Force Microscope (AFM) was processed. Feeding mouse with those microencapsulation by gastric larvae, and after 5 days, detecting its expression in mouse intestine by RT-PCR and indirect immunofluorescence (IIF). Results show that the porcine ZP-3α eukaryotic expression vector pVAX1-pZP3α had been constructed correctly, and the chitosan-DNA expressing ZP microencapsulation was prepd. successfully. After 5 days of feeding mouse, the transcription and expression of those DNA vaccines were found in mouse alvine chorion. The prepn. of chitosan/pVAX1-pZP3α plasmid DNA nanoparticles and its expression in mice will help to investigate the feasibility of ZP DNA vaccine to induce oviduct local mucosal immunity against ZP to block the fertilization without causing ovarian dysfunction, which will provide new ideas and ways for research and exploiting more effective, more convenient oral contraceptive vaccines.

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14. 14

    Carroll, E. C.; Jin, L.; Mori, A.; Munoz-Wolf, N.; Oleszycka, E.; Moran, H. B. T.; Mansouri, S.; McEntee, C. P.; Lambe, E.; Agger, E. M.; Andersen, P.; Cunningham, C.; Hertzog, P.; Fitzgerald, K. A.; Bowie, A. G.; Lavelle, E. C. The Vaccine Adjuvant Chitosan Promotes Cellular Immunity via DNA Sensor cGAS-STING-Dependent Induction of Type I Interferons. Immunity 2016, 44 (3), 597– 608,  DOI: 10.1016/j.immuni.2016.02.004

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    14

    The Vaccine Adjuvant Chitosan Promotes Cellular Immunity via DNA Sensor cGAS-STING-Dependent Induction of Type I Interferons

    Carroll, Elizabeth. C.; Jin, Lei; Mori, Andres; Munoz-Wolf, Natalia; Oleszycka, Ewa; Moran, Hannah B. T.; Mansouri, Samira; McEntee, Craig P.; Lambe, Eimear; Agger, Else Marie; Andersen, Peter; Cunningham, Colm; Hertzog, Paul; Fitzgerald, Katherine A.; Bowie, Andrew G.; Lavelle, Ed C.

    Immunity (2016), 44 (3), 597-608CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)

    The cationic polysaccharide chitosan is an attractive candidate adjuvant capable of driving potent cell-mediated immunity, but the mechanism by which it acts is not clear. We show that chitosan promotes dendritic cell maturation by inducing type I interferons (IFNs) and enhances antigen-specific T helper 1 (Th1) responses in a type I IFN receptor-dependent manner. The induction of type I IFNs, IFN-stimulated genes and dendritic cell maturation by chitosan required the cytoplasmic DNA sensor cGAS and STING, implicating this pathway in dendritic cell activation. Addnl., this process was dependent on mitochondrial reactive oxygen species and the presence of cytoplasmic DNA. Chitosan-mediated enhancement of antigen specific Th1 and IgG2c responses following vaccination was dependent on both cGAS and STING. These findings demonstrate that a cationic polymer can engage the STING-cGAS pathway to trigger innate and adaptive immune responses.

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15. 15

    Grifoni, A.; Weiskopf, D.; Ramirez, S. I.; Mateus, J.; Dan, J. M.; Moderbacher, C. R.; Rawlings, S. A.; Sutherland, A.; Premkumar, L.; Jadi, R. S.; Marrama, D.; de Silva, A. M.; Frazier, A.; Carlin, A. F.; Greenbaum, J. A.; Peters, B.; Krammer, F.; Smith, D. M.; Crotty, S.; Sette, A. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 2020, 181 (7), 1489– 1501 e15,  DOI: 10.1016/j.cell.2020.05.015

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    15

    Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

    Grifoni, Alba; Weiskopf, Daniela; Ramirez, Sydney I.; Mateus, Jose; Dan, Jennifer M.; Moderbacher, Carolyn Rydyznski; Rawlings, Stephen A.; Sutherland, Aaron; Premkumar, Lakshmanane; Jadi, Ramesh S.; Marrama, Daniel; de Silva, Aravinda M.; Frazier, April; Carlin, Aaron F.; Greenbaum, Jason A.; Peters, Bjoern; Krammer, Florian; Smith, Davey M.; Crotty, Shane; Sette, Alessandro

    Cell (Cambridge, MA, United States) (2020), 181 (7), 1489-1501.e15CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide "megapools," circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, resp. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%-27% of the total CD4+ response, with addnl. responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in ∼40%-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating "common cold" coronaviruses and SARS-CoV-2.

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16. 16

    Moss, P. The T cell immune response against SARS-CoV-2. Nat. Immunol. 2022, 23 (2), 186– 193,  DOI: 10.1038/s41590-021-01122-w

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    16

    The T cell immune response against SARS-CoV-2

    Moss, Paul

    Nature Immunology (2022), 23 (2), 186-193CODEN: NIAMCZ; ISSN:1529-2908. (Nature Portfolio)

    The adaptive immune response is a major determinant of the clin. outcome after SARS-CoV-2 infection and underpins vaccine efficacy. T cell responses develop early and correlate with protection but are relatively impaired in severe disease and are assocd. with intense activation and lymphopenia. A subset of T cells primed against seasonal coronaviruses cross reacts with SARS-CoV-2 and may contribute to clin. protection, particularly in early life. T cell memory encompasses broad recognition of viral proteins, estd. at around 30 epitopes within each individual, and seems to be well sustained so far. This breadth of recognition can limit the impact of individual viral mutations and is likely to underpin protection against severe disease from viral variants, including Omicron. Current COVID-19 vaccines elicit robust T cell responses that likely contribute to remarkable protection against hospitalization or death, and novel or heterologous regimens offer the potential to further enhance cellular responses. T cell immunity plays a central role in the control of SARS-CoV-2 and its importance may have been relatively underestimated thus far.

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17. 17

    Sheng, T.; Luo, B.; Zhang, W.; Ge, X.; Yu, J.; Zhang, Y.; Gu, Z. Microneedle-Mediated Vaccination: Innovation and Translation. Adv. Drug Deliv. Rev. 2021, 179, 113919  DOI: 10.1016/j.addr.2021.113919

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    17

    Microneedle-Mediated Vaccination: Innovation and Translation

    Sheng, Tao; Luo, Bowen; Zhang, Wentao; Ge, Xinyang; Yu, Jicheng; Zhang, Yuqi; Gu, Zhen

    Advanced Drug Delivery Reviews (2021), 179 (), 113919CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)

    A review. Vaccine administration by s.c. or i.m. injection is the most commonly prescribed route for inoculation, however, it is often assocd. with some deficiencies such as low compliance, high professionalism, and risk of infection. Therefore, the application of microneedles for vaccine delivery has gained widespread interests in the past few years due to its high compliance, minimal invasiveness, and convenience. This review focuses on recent advances in the development and application of microneedles for vaccination based on different delivery strategies, and introduces the current status of microneedle-mediated vaccination in clin. translation. The prospects for its application including opportunities and challenges are further discussed.

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18. 18

    Korkmaz, E.; Balmert, S. C.; Carey, C. D.; Erdos, G.; Falo, L. D., Jr. Emerging skin-targeted drug delivery strategies to engineer immunity: A focus on infectious diseases. Expert Opin. Drug Deliv. 2021, 18 (2), 151– 167,  DOI: 10.1080/17425247.2021.1823964

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    18

    Emerging skin-targeted drug delivery strategies to engineer immunity: A focus on infectious diseases

    Korkmaz, Emrullah; Balmert, Stephen C.; Carey, Cara Donahue; Erdos, Geza; Falo, Louis D. Jr

    Expert Opinion on Drug Delivery (2021), 18 (2), 151-167CODEN: EODDAW; ISSN:1742-5247. (Taylor & Francis Ltd.)

    A review. Introduction: Infectious pathogens are global disrupters. Progress in biomedical science and technol. has expanded the public health arsenal against infectious diseases. Specifically, vaccination has reduced the burden of infectious pathogens. Engineering systemic immunity by harnessing the cutaneous immune network has been particularly attractive since the skin is an easily accessible immune-responsive organ. Recent advances in skin-targeted drug delivery strategies have enabled safe, patient-friendly, and controlled deployment of vaccines to cutaneous microenvironments for inducing long-lived pathogen-specific immunity to mitigate infectious diseases, including COVID-19. Areas covered: This review briefly discusses the basics of cutaneous immunomodulation and provides a concise overview of emerging skin-targeted drug delivery systems that enable safe, minimally invasive, and effective intracutaneous administration of vaccines for engineering systemic immune responses to combat infectious diseases. Expert opinion: In-situ engineering of the cutaneous microenvironment using emerging skin-targeted vaccine delivery systems offers remarkable potential to develop diverse immunization strategies against pathogens. Mechanistic studies with std. correlates of vaccine efficacy will be important to compare innovative intracutaneous drug delivery strategies to each other and to existing clin. approaches. Cost-benefit analyses will be necessary for developing effective commercialization strategies. Significant involvement of industry and/or government will be imperative for successfully bringing novel skin-targeted vaccine delivery methods to market for their widespread use.

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19. 19

    Depelsenaire, A. C. I.; Meliga, S. C.; McNeilly, C. L.; Pearson, F. E.; Coffey, J. W.; Haigh, O. L.; Flaim, C. J.; Frazer, I. H.; Kendall, M. A. F. Colocalization of cell death with antigen deposition in skin enhances vaccine immunogenicity. J. Invest. Dermatol. 2014, 134 (9), 2361– 2370,  DOI: 10.1038/jid.2014.174

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    19

    Colocalization of Cell Death with Antigen Deposition in Skin Enhances Vaccine Immunogenicity

    Depelsenaire, Alexandra C. I.; Meliga, Stefano C.; McNeilly, Celia L.; Pearson, Frances E.; Coffey, Jacob W.; Haigh, Oscar L.; Flaim, Christopher J.; Frazer, Ian H.; Kendall, Mark A. F.

    Journal of Investigative Dermatology (2014), 134 (9), 2361-2370CODEN: JIDEAE; ISSN:0022-202X. (Nature Publishing Group)

    Vaccines delivered to the skin by microneedles-with and without adjuvants-have increased immunogenicity with lower doses than std. vaccine delivery techniques such as i.m. or intradermal injection. However, the mechanisms underlying this skin-mediated "adjuvant" effect are not clear. Here, we show that the dynamic application of a microprojection array (the Nanopatch) to skin generates localized transient stresses invoking cell death around each projection. Nanopatch application caused significantly higher levels (∼65-fold) of cell death in murine ear skin than i.d. injection using a hypodermic needle. Measured skin cell death is assocd. with modeled stresses ∼1-10 MPa. Nanopatch-immunized groups also yielded consistently higher anti-IgG endpoint titers (up to 50-fold higher) than i.d. groups after delivery of a split virion influenza vaccine. Importantly, colocalization of cell death with nearby live skin cells and delivered antigen was necessary for immunogenicity enhancement. These results suggest a correlation between cell death caused by the Nanopatch with increased immunogenicity. We propose that the localized cell death serves as a "phys. immune enhancer" for the adjacent viable skin cells, which also receive antigen from the projections. This natural immune enhancer effect has the potential to mitigate or replace chem.-based adjuvants in vaccines.

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20. 20

    Rock, K. L.; York, I. A.; Goldberg, A. L. Post-proteasomal antigen processing for major histocompatibility complex class I presentation. Nat. Immunol. 2004, 5 (7), 670– 7,  DOI: 10.1038/ni1089

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    20

    Post-proteasomal antigen processing for major histocompatibility complex class I presentation

    Rock, Kenneth L.; York, Ian A.; Goldberg, Alfred L.

    Nature Immunology (2004), 5 (7), 670-677CODEN: NIAMCZ; ISSN:1529-2908. (Nature Publishing Group)

    A review. Peptides presented by major histocompatibility complex class I mols. are derived mainly from cytosolic oligopeptides generated by proteasomes during the degrdn. of intracellular proteins. Proteasomal cleavages generate the final C terminus of these epitopes. Although proteasomes may produce mature epitopes that are eight to ten residues in length, they more often generate N-extended precursors that are too long to bind to major histocompatibility complex class I mols. Such precursors are trimmed in the cytosol or in the endoplasmic reticulum by aminopeptidases that generate the N terminus of the presented epitope. Peptidases can also destroy epitopes by trimming peptides to below the size needed for presentation. In the cytosol, endopeptidases, esp. thimet oligopeptidase, and aminopeptidases degrade many proteasomal products, thereby limiting the supply of many antigenic peptides. Thus, the extent of antigen presentation depends on the balance between several proteolytic processes that may generate or destroy epitopes.

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21. 21

    Mateus, J.; Grifoni, A.; Tarke, A.; Sidney, J.; Ramirez, S. I.; Dan, J. M.; Burger, Z. C.; Rawlings, S. A.; Smith, D. M.; Phillips, E.; Mallal, S.; Lammers, M.; Rubiro, P.; Quiambao, L.; Sutherland, A.; Yu, E. D.; da Silva Antunes, R.; Greenbaum, J.; Frazier, A.; Markmann, A. J.; Premkumar, L.; de Silva, A.; Peters, B.; Crotty, S.; Sette, A.; Weiskopf, D. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science 2020, 370 (6512), 89– 94,  DOI: 10.1126/science.abd3871

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    21

    Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans

    Mateus, Jose; Grifoni, Alba; Tarke, Alison; Sidney, John; Ramirez, Sydney I.; Dan, Jennifer M.; Burger, Zoe C.; Rawlings, Stephen A.; Smith, Davey M.; Phillips, Elizabeth; Mallal, Simon; Lammers, Marshall; Rubiro, Paul; Quiambao, Lorenzo; Sutherland, Aaron; Yu, Esther Dawen; da Silva Antunes, Ricardo; Greenbaum, Jason; Frazier, April; Markmann, Alena J.; Premkumar, Lakshmanane; de Silva, Aravinda; Peters, Bjoern; Crotty, Shane; Sette, Alessandro; Weiskopf, Daniela

    Science (Washington, DC, United States) (2020), 370 (6512), 89-94CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)

    Many unknowns exist about human immune responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. SARS-CoV-2 reactive CD4+ T cells have been reported in unexposed individuals, suggesting preexisting cross-reactive T cell memory in 20 to 50% of people. However, the source of those T cells has been speculative. Using human blood samples derived before the SARS-CoV-2 virus was discovered in 2019, we mapped 142 T cell epitopes across the SARS-CoV-2 genome to facilitate precise interrogation of the SARS-CoV-2 specific CD4+ T cell repertoire. We demonstrate a range of preexisting memory CD4+ T cells that are cross-reactive with comparable affinity to SARS-CoV-2 and the common cold coronaviruses human coronavirus (HCoV)-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1. Thus, variegated T cell memory to coronaviruses that cause the common cold may underlie at least some of the extensive heterogeneity obsd. in coronavirus disease 2019 (COVID-19) disease.

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22. 22

    Le Bert, N.; Tan, A. T.; Kunasegaran, K.; Tham, C. Y. L.; Hafezi, M.; Chia, A.; Chng, M. H. Y.; Lin, M.; Tan, N.; Linster, M.; Chia, W. N.; Chen, M. I.; Wang, L. F.; Ooi, E. E.; Kalimuddin, S.; Tambyah, P. A.; Low, J. G.; Tan, Y. J.; Bertoletti, A. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 2020, 584 (7821), 457– 462,  DOI: 10.1038/s41586-020-2550-z

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    22

    SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls

    Le Bert, Nina; Tan, Anthony T.; Kunasegaran, Kamini; Tham, Christine Y. L.; Hafezi, Morteza; Chia, Adeline; Chng, Melissa Hui Yen; Lin, Meiyin; Tan, Nicole; Linster, Martin; Chia, Wan Ni; Chen, Mark I-Cheng; Wang, Lin-Fa; Ooi, Eng Eong; Kalimuddin, Shirin; Tambyah, Paul Anantharajah; Low, Jenny Guek-Hong; Tan, Yee-Joo; Bertoletti, Antonio

    Nature (London, United Kingdom) (2020), 584 (7821), 457-462CODEN: NATUAS; ISSN:0028-0836. (Nature Research)

    Memory T cells induced by previous pathogens can shape susceptibility to, and the clin. severity of, subsequent infections. Little is known about the presence in humans of pre-existing memory T cells that have the potential to recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We studied T cell responses against the structural (nucleocapsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from COVID-19 (n = 36). In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein. Next, we showed that patients (n = 23) who recovered from SARS (the disease assocd. with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 yr after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2. We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19, or contact with individuals who had SARS and(or) COVID-19 (n = 37). SARS-CoV-2-specific T cells in uninfected donors exhibited a different pattern of immunodominance, and frequently targeted NSP7 and NSP13 as well as the N protein. Epitope characterization of NSP7-specific T cells showed the recognition of protein fragments that are conserved among animal betacoronaviruses but have low homol. to common cold human-assocd. coronaviruses. Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein. Understanding how pre-existing N- and ORF1-specific T cells that are present in the general population affect the susceptibility to and pathogenesis of SARS-CoV-2 infection is important for the management of the current COVID-19 pandemic.

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23. 23

    Selin, L. K.; Brehm, M. A.; Naumov, Y. N.; Cornberg, M.; Kim, S. K.; Clute, S. C.; Welsh, R. M. Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunity. Immunol. Rev. 2006, 211 (1), 164– 81,  DOI: 10.1111/j.0105-2896.2006.00394.x

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    23

    Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunity

    Selin, Liisa K.; Brehm, Michael A.; Naumov, Yuri N.; Cornberg, Markus; Kim, Sung-Kwon; Clute, Shalyn C.; Welsh, Raymond M.

    Immunological Reviews (2006), 211 (), 164-181CODEN: IMRED2; ISSN:0105-2896. (Blackwell Publishing Ltd.)

    A review. The main functions of memory T cells are to provide protection upon re-exposure to a pathogen and to prevent the re-emergence of low-grade persistent pathogens. Memory T cells achieve these functions through their high frequency and elevated activation state, which lead to rapid responses upon antigenic challenge. The significance and characteristics of memory CD8+ T cells in viral infections have been studied extensively. In many of these studies of T-cell memory, exptl. viral immunologists go to great lengths to assure that their animal colonies are free of endogenous pathogens in order to design reproducible expts. These exptl. results are then thought to provide the basis for our understanding of human immune responses to viruses. Although these findings can be enlightening, humans are not immunol. naive, and they often have memory T-cell populations that can cross-react with and respond to a new infectious agent or cross-react with allo-antigens and influence the success of tissue transplantation. These cross-reactive T cells can become activated and modulate the immune response and outcome of subsequent heterologous infections, a phenomenon we have termed heterologous immunity. These large memory populations are also accommodated into a finite immune system, requiring that the host makes room for each new population of memory cell. It appears that memory cells are part of a continually evolving interactive network, where with each new infection there is an alteration in the frequencies, distributions, and activities of memory cells generated in response to previous infections and allo-antigens.

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24. 24

    Riou, C.; Keeton, R.; Moyo-Gwete, T.; Hermanus, T.; Kgagudi, P.; Baguma, R.; Valley-Omar, Z.; Smith, M.; Tegally, H.; Doolabh, D.; Iranzadeh, A.; Tyers, L.; Mutavhatsindi, H.; Tincho, M. B.; Benede, N.; Marais, G.; Chinhoyi, L. R.; Mennen, M.; Skelem, S.; du Bruyn, E.; Stek, C.; de Oliveira, T.; Williamson, C.; Moore, P. L.; Wilkinson, R. J.; Ntusi, N. A. B.; Burgers, W. A. Escape from recognition of SARS-CoV-2 variant spike epitopes but overall preservation of T cell immunity. Sci. Transl. Med. 2022, 14 (631), eabj6824  DOI: 10.1126/scitranslmed.abj6824

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    There is no corresponding record for this reference.
25. 25

    Choi, S. J.; Kim, D. U.; Noh, J. Y.; Kim, S.; Park, S. H.; Jeong, H. W.; Shin, E. C. T cell epitopes in SARS-CoV-2 proteins are substantially conserved in the Omicron variant. Cell. Mol. Immunol. 2022, 19 (3), 447– 448,  DOI: 10.1038/s41423-022-00838-5

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    25

    T cell epitopes in SARS-CoV-2 proteins are substantially conserved in the Omicron variant

    Choi, Seong Jin; Kim, Dong-Uk; Noh, Ji Yun; Kim, Sangwoo; Park, Su-Hyung; Jeong, Hye Won; Shin, Eui-Cheol

    Cellular & Molecular Immunology (2022), 19 (3), 447-448CODEN: CMIEAO; ISSN:1672-7681. (Nature Portfolio)

    Our current anal. demonstrates that T cell epitopes are considerably conserved in the Omicron variant and that substantial proportions of memory T cells elicited by COVID-19 vaccination or natural infection respond to the Omicron spike. These results indicate that memory T cells may provide protective immunity during reinfection or breakthrough infection with the Omicron variant.

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26. 26

    Naranbhai, V.; Nathan, A.; Kaseke, C.; Berrios, C.; Khatri, A.; Choi, S.; Getz, M. A.; Tano-Menka, R.; Ofoman, O.; Gayton, A.; Senjobe, F.; Zhao, Z.; St Denis, K. J.; Lam, E. C.; Carrington, M.; Garcia-Beltran, W. F.; Balazs, A. B.; Walker, B. D.; Iafrate, A. J.; Gaiha, G. D. T cell reactivity to the SARS-CoV-2 Omicron variant is preserved in most but not all individuals. Cell 2022, 185 (6), 1041– 1051 e6,  DOI: 10.1016/j.cell.2022.01.029

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    26

    T cell reactivity to the SARS-CoV-2 Omicron variant is preserved in most but not all individuals

    Naranbhai, Vivek; Nathan, Anusha; Kaseke, Clarety; Berrios, Cristhian; Khatri, Ashok; Choi, Shawn; Getz, Matthew A.; Tano-Menka, Rhoda; Ofoman, Onosereme; Gayton, Alton; Senjobe, Fernando; Zhao, Zezhou; St Denis, Kerri J.; Lam, Evan C.; Carrington, Mary; Garcia-Beltran, Wilfredo F.; Balazs, Alejandro B.; Walker, Bruce D.; Iafrate, A. John; Gaiha, Gaurav D.

    Cell (Cambridge, MA, United States) (2022), 185 (6), 1041-1051.e6CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    The SARS-CoV-2 Omicron variant (B.1.1.529) contains mutations that mediate escape from antibody responses, although the extent to which these substitutions in spike and non-spike proteins affect T cell recognition is unknown. T cell responses in individuals with prior infection, vaccination, both prior infection and vaccination, and boosted vaccination are largely preserved to Omicron spike and non-spike proteins. However, we also identify a subset of individuals (∼21%) with a >50% redn. in T cell reactivity to the Omicron spike. Evaluation of functional CD4+ and CD8+ memory T cell responses confirmed these findings and revealed that reduced recognition to Omicron spike is primarily obsd. within the CD8+ T cell compartment potentially due to escape from HLA binding. Booster vaccination enhanced T cell responses to Omicron spike. In contrast to neutralizing immunity, these findings suggest preservation of T cell responses to the Omicron variant, although with reduced reactivity in some individuals.

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27. 27

    Fan, F.; Zhang, X.; Zhang, Z.; Ding, Y.; Wang, L.; Xu, X.; Pan, Y.; Gong, F. Y.; Jiang, L.; Kang, L.; Ha, Z.; Lu, H.; Hou, J.; Kou, Z.; Zhao, G.; Wang, B.; Gao, X. M. Potent immunogenicity and broad-spectrum protection potential of microneedle array patch-based COVID-19 DNA vaccine candidates encoding dimeric RBD chimera of SARS-CoV and SARS-CoV-2 variants. Emerg. Microbes Infect. 2023, 12 (1), 2202269  DOI: 10.1080/22221751.2023.2202269

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    27

    Potent immunogenicity and broad-spectrum protection potential of microneedle array patch-based COVID-19 DNA vaccine candidates encoding dimeric RBD chimera of SARS-CoV and SARS-CoV-2 variants

    Fan, Feng; Zhang, Xin; Zhang, Zhiyu; Ding, Yuan; Wang, Limei; Xu, Xin; Pan, Yaying; Gong, Fang-Yuan; Jiang, Lin; Kang, Lingyu; Ha, Zhuo; Lu, Huijun; Hou, Jiawang; Kou, Zhihua; Zhao, Gan; Wang, Bin; Gao, Xiao-Ming

    Emerging Microbes & Infections (2023), 12 (1), 2202269/1-2202269/16CODEN: EMIMC4; ISSN:2222-1751. (Taylor & Francis Ltd.)

    Breakthrough infections by SARS-CoV-2 variants pose a global challenge to COVID-19 pandemic control, and the development of more effective vaccines of broad-spectrum protection is needed. In this study, we constructed pVAX1-based plasmids encoding receptor-binding domain (RBD) chimera of SARS-CoV-1 and SARS-CoV-2 variants, including pAD1002 (encoding RBDSARS/BA1), pAD1003 (encoding RBDSARS/Beta) and pAD131 (encoding RBDBA1/Beta). Plasmids pAD1002 and pAD131 were far more immunogenic than pAD1003 in terms of eliciting RBD-specific IgG when i.m. administered without electroporation. Furthermore, dissolvable microneedle array patches (MAP) greatly enhanced the immunogenicity of these DNA constructs in mice and rabbits. MAP laden with pAD1002 (MAP-1002) significantly outperformed inactivated SARS-CoV-2 virus vaccine in inducing RBD-specific IFN-γ+ effector and memory T cells, and generated T lymphocytes of different homing patterns compared to that induced by electroporated DNA in mice. In consistence with the high titer neutralization results of MAP-1002 antisera against SARS-CoV-2 pseudoviruses, MAP-1002 protected human ACE2-transgenic mice from Omicron BA.1 challenge. Collectively, MAP-based DNA constructs encoding chimeric RBDs of SARS-CoV-1 and SARS-CoV-2 variants, as represented by MAP-1002, are potential COVID-19 vaccine candidates worthy further translational study.

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28. 28

    Castro Dopico, X.; Ols, S.; Lore, K.; Karlsson Hedestam, G. B. Immunity to SARS-CoV-2 induced by infection or vaccination. J. Intern. Med. 2022, 291 (1), 32– 50,  DOI: 10.1111/joim.13372

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    28

    Immunity to SARS-CoV-2 induced by infection or vaccination

    Castro Dopico, Xaquin; Ols, Sebastian; Lore, Karin; Karlsson Hedestam, Gunilla B.

    Journal of Internal Medicine (2022), 291 (1), 32-50CODEN: JINMEO; ISSN:0954-6820. (Wiley-Blackwell)

    A review. Adaptive immune responses play crit. roles in viral clearance and protection against re-infection, and SARS-CoV-2 is no exception. What is exceptional, is the rapid characterization of the immune response to the virus performed by researchers during the first 20 mo of the pandemic. This has given us a more detailed understanding about SARS-CoV-2 than we have about many viruses that have been with us for a long time. Furthermore, effective COVID-19 vaccines were developed in record time, and their rollout worldwide is already making a significant difference, although major challenges remain in terms of equal access. The pandemic has engaged scientists and the public alike, and terms such as seroprevalence, neutralizing antibodies, antibody escape and vaccine certificates have become familiar to a broad community. Here, we review key findings concerning B cell and antibody (Ab) responses to SARS-CoV-2, focusing on non-severe cases and anti-spike (S) Ab responses in particular, the latter being central to protective immunity induced by infection or vaccination. The emergence of viral variants that have acquired mutations in S acutely highlights the need for continued characterization of both emerging variants and Ab responses against these during the evolving pathogen-immune system arms race.

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    Dutta, N. K.; Mazumdar, K.; Gordy, J. T. The Nucleocapsid Protein of SARS-CoV-2: a Target for Vaccine Development. J. Virol. 2020, 94 (13), 647-20,  DOI: 10.1128/JVI.00647-20

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    There is no corresponding record for this reference.
30. 30

    Ni, L.; Ye, F.; Cheng, M. L.; Feng, Y.; Deng, Y. Q.; Zhao, H.; Wei, P.; Ge, J.; Gou, M.; Li, X.; Sun, L.; Cao, T.; Wang, P.; Zhou, C.; Zhang, R.; Liang, P.; Guo, H.; Wang, X.; Qin, C. F.; Chen, F.; Dong, C. Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals. Immunity 2020, 52 (6), 971– 977 e3,  DOI: 10.1016/j.immuni.2020.04.023

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    Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals

    Ni, Ling; Ye, Fang; Cheng, Meng-Li; Feng, Yu; Deng, Yong-Qiang; Zhao, Hui; Wei, Peng; Ge, Jiwan; Gou, Mengting; Li, Xiaoli; Sun, Lin; Cao, Tianshu; Wang, Pengzhi; Zhou, Chao; Zhang, Rongrong; Liang, Peng; Guo, Han; Wang, Xinquan; Qin, Cheng-Feng; Chen, Fang; Dong, Chen

    Immunity (2020), 52 (6), 971-977.e3CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)

    The World Health Organization has declared SARS-CoV-2 virus outbreak a worldwide pandemic. However, there is very limited understanding on the immune responses, esp. adaptive immune responses to SARS-CoV-2 infection. Here, we collected blood from COVID-19 patients who have recently become virus-free, and therefore were discharged, and detected SARS-CoV-2-specific humoral and cellular immunity in eight newly discharged patients. Follow-up anal. on another cohort of six patients 2 wk post discharge also revealed high titers of IgG antibodies. In all 14 patients tested, 13 displayed serum-neutralizing activities in a pseudotype entry assay. Notably, there was a strong correlation between neutralization antibody titers and the nos. of virus-specific T cells. Our work provides a basis for further anal. of protective immunity to SARS-CoV-2, and understanding the pathogenesis of COVID-19, esp. in the severe cases. It also has implications in developing an effective vaccine to SARS-CoV-2 infection.

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    Peng, Y.; Mentzer, A. J.; Liu, G.; Yao, X.; Yin, Z.; Dong, D.; Dejnirattisai, W.; Rostron, T.; Supasa, P.; Liu, C.; Lopez-Camacho, C.; Slon-Campos, J.; Zhao, Y.; Stuart, D. I.; Paesen, G. C.; Grimes, J. M.; Antson, A. A.; Bayfield, O. W.; Hawkins, D.; Ker, D. S.; Wang, B.; Turtle, L.; Subramaniam, K.; Thomson, P.; Zhang, P.; Dold, C.; Ratcliff, J.; Simmonds, P.; de Silva, T.; Sopp, P.; Wellington, D.; Rajapaksa, U.; Chen, Y. L.; Salio, M.; Napolitani, G.; Paes, W.; Borrow, P.; Kessler, B. M.; Fry, J. W.; Schwabe, N. F.; Semple, M. G.; Baillie, J. K.; Moore, S. C.; Openshaw, P. J. M.; Ansari, M. A.; Dunachie, S.; Barnes, E.; Frater, J.; Kerr, G.; Goulder, P.; Lockett, T.; Levin, R.; Zhang, Y.; Jing, R.; Ho, L. P.; Oxford Immunology Network Covid-19 Response, T. c. C.; Investigators, I. C.; Cornall, R. J.; Conlon, C. P.; Klenerman, P.; Screaton, G. R.; Mongkolsapaya, J.; McMichael, A.; Knight, J. C.; Ogg, G.; Dong, T. Broad and strong memory CD4(+) and CD8(+) T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19. Nat. Immunol. 2020, 21 (11), 1336– 1345,  DOI: 10.1038/s41590-020-0782-6

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    Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19

    Peng, Yanchun; Mentzer, Alexander J.; Liu, Guihai; Yao, Xuan; Yin, Zixi; Dong, Danning; Dejnirattisai, Wanwisa; Rostron, Timothy; Supasa, Piyada; Liu, Chang; Lopez-Camacho, Cesar; Slon-Campos, Jose; Zhao, Yuguang; Stuart, David I.; Paesen, Guido C.; Grimes, Jonathan M.; Antson, Alfred A.; Bayfield, Oliver W.; Hawkins, Dorothy E. D. P.; Ker, De-Sheng; Wang, Beibei; Turtle, Lance; Subramaniam, Krishanthi; Thomson, Paul; Zhang, Ping; Dold, Christina; Ratcliff, Jeremy; Simmonds, Peter; de Silva, Thushan; Sopp, Paul; Wellington, Dannielle; Rajapaksa, Ushani; Chen, Yi-Ling; Salio, Mariolina; Napolitani, Giorgio; Paes, Wayne; Borrow, Persephone; Kessler, Benedikt M.; Fry, Jeremy W.; Schwabe, Nikolai F.; Semple, Malcolm G.; Baillie, J. Kenneth; Moore, Shona C.; Openshaw, Peter J. M.; Ansari, M. Azim; Dunachie, Susanna; Barnes, Eleanor; Frater, John; Kerr, Georgina; Goulder, Philip; Lockett, Teresa; Levin, Robert; Zhang, Yonghong; Jing, Ronghua; Ho, Ling-Pei; Cornall, Richard J.; Conlon, Christopher P.; Klenerman, Paul; Screaton, Gavin R.; Mongkolsapaya, Juthathip; McMichael, Andrew; Knight, Julian C.; Ogg, Graham; Dong, Tao

    Nature Immunology (2020), 21 (11), 1336-1345CODEN: NIAMCZ; ISSN:1529-2908. (Nature Research)

    Abstr.: The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides contg. CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide-MHC pentamer-pos. cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were obsd. The identification of T cell responses assocd. with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.

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32. 32

    Harris, P. E.; Brasel, T.; Massey, C.; Herst, C. V.; Burkholz, S.; Lloyd, P.; Blankenberg, T.; Bey, T. M.; Carback, R.; Hodge, T.; Ciotlos, S.; Wang, L.; Comer, J. E.; Rubsamen, R. M. A Synthetic Peptide CTL Vaccine Targeting Nucleocapsid Confers Protection from SARS-CoV-2 Challenge in Rhesus Macaques. Vaccines (Basel) 2021, 9 (5), 520,  DOI: 10.3390/vaccines9050520

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    A synthetic peptide CTL vaccine targeting nucleocapsid confers protection from SARS-CoV-2 challenge in rhesus macaques

    Harris, Paul E.; Brasel, Trevor; Massey, Christopher; Herst, C. V.; Burkholz, Scott; Lloyd, Peter; Blankenberg, Tikoes; Bey, Thomas M.; Carback, Richard; Hodge, Thomas; Ciotlos, Serban; Wang, Lu; Comer, Jason E.; Rubsamen, Reid M.

    Vaccines (Basel, Switzerland) (2021), 9 (5), 520CODEN: VBSABP; ISSN:2076-393X. (MDPI AG)

    Background: Persistent transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a COVID-19 pandemic. Several vaccines, conceived in 2020, that evoke protective spike antibody responses are being deployed in mass public health vaccination programs. Recent data suggests, however, that as sequence variation in the spike genome accumulates, some vaccines may lose efficacy. Methods: Using a macaque model of SARS-CoV-2 infection, we tested the efficacy of a peptide-based vaccine targeting MHC class I epitopes on the SARS-CoV-2 nucleocapsid protein. We administered biodegradable microspheres with synthetic peptides and adjuvants to rhesus macaques. Unvaccinated control and vaccinated macaques were challenged with 1 x 108 TCID50 units of SARS-CoV-2, followed by assessment of clin. symptoms and viral load, chest radiographs, and sampling of peripheral blood and bronchoalveolar lavage (BAL) fluid for downstream anal. Results: Vaccinated animals were free of pneumonia-like infiltrates characteristic of SARS-CoV-2 infection and presented with lower viral loads relative to controls. Gene expression in cells collected from BAL samples of vaccinated macaques revealed a unique signature assocd. with enhanced development of adaptive immune responses relative to control macaques. Conclusions: We demonstrate that a room temp. stable peptide vaccine based on known immunogenic HLA class I bound CTL epitopes from the nucleocapsid protein can provide protection against SARS-CoV-2 infection in nonhuman primates.

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    Matchett, W. E.; Joag, V.; Stolley, J. M.; Shepherd, F. K.; Quarnstrom, C. F.; Mickelson, C. K.; Wijeyesinghe, S.; Soerens, A. G.; Becker, S.; Thiede, J. M.; Weyu, E.; O’Flanagan, S. D.; Walter, J. A.; Vu, M. N.; Menachery, V. D.; Bold, T. D.; Vezys, V.; Jenkins, M. K.; Langlois, R. A.; Masopust, D. Cutting Edge: Nucleocapsid Vaccine Elicits Spike-Independent SARS-CoV-2 Protective Immunity. J. Immunol. 2021, 207 (2), 376– 379,  DOI: 10.4049/jimmunol.2100421

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    Cutting edge: nucleocapsid vaccine elicits spike-independent SARS-CoV-2 protective immunity

    Matchett, William E.; Joag, Vineet; Stolley, J. Michael; Shepherd, Frances K.; Quarnstrom, Clare F.; Mickelson, Clayton K.; Wijeyesinghe, Sathi; Soerens, Andrew G.; Becker, Samuel; Thiede, Joshua M.; Weyu, Eyob; O'Flanagan, Stephen D.; Walter, Jennifer A.; Vu, Michelle N.; Menachery, Vineet D.; Bold, Tyler D.; Vezys, Vaiva; Jenkins, Marc K.; Langlois, Ryan A.; Masopust, David

    Journal of Immunology (2021), 207 (2), 376-379CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Neutralizing Abs target the receptor binding domain of the spike (S) protein, a focus of successful vaccine efforts. Concerns have arisen that S-specific vaccine immunity may fail to neutralize emerging variants. We show that vaccination with a human adenovirus type 5 vector expressing the SARS-CoV-2 nucleocapsid (N) protein can establish protective immunity, defined by reduced wt. loss and viral load, in both Syrian hamsters and K18-hACE2 mice. Challenge of vaccinated mice was assocd. with rapid N-specific T cell recall responses in the respiratory mucosa. This study supports the rationale for including addnl. viral Ags in SARS-CoV-2 vaccines, even if they are not a target of neutralizing Abs, to broaden epitope coverage and immune effector mechanisms.

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34. 34

    Chiuppesi, F.; Nguyen, V. H.; Park, Y.; Contreras, H.; Karpinski, V.; Faircloth, K.; Nguyen, J.; Kha, M.; Johnson, D.; Martinez, J.; Iniguez, A.; Zhou, Q.; Kaltcheva, T.; Frankel, P.; Kar, S.; Sharma, A.; Andersen, H.; Lewis, M. G.; Shostak, Y.; Wussow, F.; Diamond, D. J. Synthetic multiantigen MVA vaccine COH04S1 protects against SARS-CoV-2 in Syrian hamsters and non-human primates. NPJ Vaccines 2022, 7 (1), 7,  DOI: 10.1038/s41541-022-00436-6

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    Synthetic multiantigen MVA vaccine COH04S1 protects against SARS-CoV-2 in Syrian hamsters and non-human primates

    Chiuppesi, Flavia; Nguyen, Vu H.; Park, Yoonsuh; Contreras, Heidi; Karpinski, Veronica; Faircloth, Katelyn; Nguyen, Jenny; Kha, Mindy; Johnson, Daisy; Martinez, Joy; Iniguez, Angelina; Zhou, Qiao; Kaltcheva, Teodora; Frankel, Paul; Kar, Swagata; Sharma, Ankur; Andersen, Hanne; Lewis, Mark G.; Shostak, Yuriy; Wussow, Felix; Diamond, Don J.

    npj Vaccines (2022), 7 (1), 7CODEN: VACCBC; ISSN:2059-0105. (Nature Portfolio)

    Second-generation COVID-19 vaccines could contribute to establish protective immunity against SARS-CoV-2 and its emerging variants. We developed COH04S1, a synthetic multiantigen modified vaccinia Ankara-based SARS-CoV-2 vaccine that co-expresses spike and nucleocapsid antigens. Here, we report COH04S1 vaccine efficacy in animal models. We demonstrate that i.m. or intranasal vaccination of Syrian hamsters with COH04S1 induces robust Th1-biased antigen-specific humoral immunity and cross-neutralizing antibodies (NAb) and protects against wt. loss, lower respiratory tract infection, and lung injury following intranasal SARS-CoV-2 challenge. Moreover, we demonstrate that single-dose or two-dose vaccination of non-human primates with COH04S1 induces robust antigen-specific binding antibodies, NAb, and Th1-biased T cells, protects against both upper and lower respiratory tract infection following intranasal/intratracheal SARS-CoV-2 challenge, and triggers potent post-challenge anamnestic antiviral responses. These results demonstrate COH04S1-mediated vaccine protection in animal models through different vaccination routes and dose regimens, complementing ongoing investigation of this multiantigen SARS-CoV-2 vaccine in clin. trials.

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    Afkhami, S.; D’Agostino, M. R.; Zhang, A.; Stacey, H. D.; Marzok, A.; Kang, A.; Singh, R.; Bavananthasivam, J.; Ye, G.; Luo, X.; Wang, F.; Ang, J. C.; Zganiacz, A.; Sankar, U.; Kazhdan, N.; Koenig, J. F. E.; Phelps, A.; Gameiro, S. F.; Tang, S.; Jordana, M.; Wan, Y.; Mossman, K. L.; Jeyanathan, M.; Gillgrass, A.; Medina, M. F. C.; Smaill, F.; Lichty, B. D.; Miller, M. S.; Xing, Z. Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2. Cell 2022, 185 (5), 896– 915 e19,  DOI: 10.1016/j.cell.2022.02.005

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    Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2

    Afkhami, Sam; D'Agostino, Michael R.; Zhang, Ali; Stacey, Hannah D.; Marzok, Art; Kang, Alisha; Singh, Ramandeep; Bavananthasivam, Jegarubee; Ye, Gluke; Luo, Xiangqian; Wang, Fuan; Ang, Jann C.; Zganiacz, Anna; Sankar, Uma; Kazhdan, Natallia; Koenig, Joshua F. E.; Phelps, Allyssa; Gameiro, Steven F.; Tang, Shangguo; Jordana, Manel; Wan, Yonghong; Mossman, Karen L.; Jeyanathan, Mangalakumari; Gillgrass, Amy; Medina, Maria Fe C.; Smaill, Fiona; Lichty, Brian D.; Miller, Matthew S.; Xing, Zhou

    Cell (Cambridge, MA, United States) (2022), 185 (5), 896-915.e19CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered i.m. and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. Single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to i.m. immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.

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    Liu, L.; Zhong, Q.; Tian, T.; Dubin, K.; Athale, S. K.; Kupper, T. S. Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity. Nat. Med. 2010, 16 (2), 224– 7,  DOI: 10.1038/nm.2078

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    Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity

    Liu, Luzheng; Zhong, Qiong; Tian, Tian; Dubin, Krista; Athale, Shruti K.; Kupper, Thomas S.

    Nature Medicine (New York, NY, United States) (2010), 16 (2), 224-227CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)

    Variola major (smallpox) infection claimed hundreds of millions lives before it was eradicated by a simple vaccination strategy: epicutaneous application of the related orthopoxvirus vaccinia virus (VACV) to superficially injured skin (skin scarification, s.s.). However, the remarkable success of this strategy was attributed to the immunogenicity of VACV rather than to the unique mode of vaccine delivery. The authors now show that VACV immunization via s.s., but not conventional injection routes, is essential for the generation of superior T cell-mediated immune responses that provide complete protection against subsequent challenges, independent of neutralizing antibodies. Skin-resident effector memory T cells (TEM cells) provide complete protection against cutaneous challenge, whereas protection against lethal respiratory challenge requires both respiratory mucosal TEM cells and central memory T cells (TCM cells). Vaccination with recombinant VACV (rVACV) expressing a tumor antigen was protective against tumor challenge only if delivered via the s.s. route; it was ineffective if delivered by hypodermic injection. The clin. safer nonreplicative modified vaccinia Ankara virus (MVA) also generated far superior protective immunity when delivered via the s.s. route compared to i.m. injection as used in MVA clin. trials. Thus, delivery of rVACV-based vaccines, including MVA vaccines, through phys. disrupted epidermis has clear-cut advantages over conventional vaccination via hypodermic injection.

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    Mikhak, Z.; Strassner, J. P.; Luster, A. D. Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4. J. Exp. Med. 2013, 210 (9), 1855– 69,  DOI: 10.1084/jem.20130091

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    Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4

    Mikhak, Zamaneh; Strassner, James P.; Luster, Andrew D.

    Journal of Experimental Medicine (2013), 210 (9), 1855-1869CODEN: JEMEAV; ISSN:0022-1007. (Rockefeller University Press)

    T cell trafficking into the lung is crit. for lung immunity, but the mechanisms that mediate T cell lung homing are not well understood. Here, we show that lung dendritic cells (DCs) imprint T cell lung homing, as lung DC-activated T cells traffic more efficiently into the lung in response to inhaled antigen and at homeostasis compared with T cells activated by DCs from other tissues. Consequently, lung DC-imprinted T cells protect against influenza more effectively than do gut and skin DC-imprinted T cells. Lung DCs imprint the expression of CCR4 on T cells, and CCR4 contributes to T cell lung imprinting. Lung DC-activated, CCR4-deficient T cells fail to traffic into the lung as efficiently and to protect against influenza as effectively as lung DC-activated, CCR4-sufficient T cells. Thus, lung DCs imprint T cell lung homing and promote lung immunity in part through CCR4.

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38. 38

    Dijkman, K.; Aguilo, N.; Boot, C.; Hofman, S. O.; Sombroek, C. C.; Vervenne, R. A. W.; Kocken, C. H. M.; Marinova, D.; Thole, J.; Rodriguez, E.; Vierboom, M. P. M.; Haanstra, K. G.; Puentes, E.; Martin, C.; Verreck, F. A. W. Pulmonary MTBVAC vaccination induces immune signatures previously correlated with prevention of tuberculosis infection. Cell Rep. Med. 2021, 2 (1), 100187  DOI: 10.1016/j.xcrm.2020.100187

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    Pulmonary MTBVAC vaccination induces immune signatures previously correlated with prevention of tuberculosis infection

    Dijkman, Karin; Aguilo, Nacho; Boot, Charelle; Hofman, Sam O.; Sombroek, Claudia C.; Vervenne, Richard A. W.; Kocken, Clemens H. M.; Marinova, Dessislava; Thole, Jelle; Rodriguez, Esteban; Vierboom, Michel P. M.; Haanstra, Krista G.; Puentes, Eugenia; Martin, Carlos; Verreck, Frank A. W.

    Cell Reports Medicine (2021), 2 (1), 100187CODEN: CRMEDE; ISSN:2666-3791. (Elsevier Inc.)

    To fight tuberculosis, better vaccination strategies are needed. Live attenuated Mycobacterium tuberculosis-derived vaccine, MTBVAC, is a promising candidate in the pipeline, proven to be safe and immunogenic in humans so far. Independent studies have shown that pulmonary mucosal delivery of Bacillus Calmette-Guerin (BCG), the only tuberculosis (TB) vaccine available today, confers superior protection over std. intradermal immunization. Here we demonstrate that mucosal MTBVAC is well tolerated, eliciting polyfunctional T helper type 17 cells, interleukin-10, and Igs in the airway and yielding a broader antigenic profile than BCG in rhesus macaques. Beyond our previous work, we show that local Igs, induced by MTBVAC and BCG, bind to M. tuberculosis and enhance pathogen uptake. Furthermore, after pulmonary vaccination, but not M. tuberculosis infection, local T cells expressed high levels of mucosal homing and tissue residency markers. Our data show that pulmonary MTBVAC administration has the potential to enhance its efficacy and justifies further exploration of mucosal vaccination strategies in preclin. efficacy studies.

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    Pan, Y.; Liu, L.; Tian, T.; Zhao, J.; Park, C. O.; Lofftus, S. Y.; Stingley, C. A.; Yan, Y.; Mei, S.; Liu, X.; Kupper, T. S. Epicutaneous immunization with modified vaccinia Ankara viral vectors generates superior T cell immunity against a respiratory viral challenge. NPJ Vaccines 2021, 6 (1), 1,  DOI: 10.1038/s41541-020-00265-5

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    39

    Epicutaneous immunization with modified vaccinia Ankara viral vectors generates superior T cell immunity against a respiratory viral challenge

    Pan, Youdong; Liu, Luzheng; Tian, Tian; Zhao, Jingxia; Park, Chang Ook; Lofftus, Serena Y.; Stingley, Claire A.; Yan, Yu; Mei, Shenglin; Liu, Xing; Kupper, Thomas S.

    npj Vaccines (2021), 6 (1), 1CODEN: VACCBC; ISSN:2059-0105. (Nature Research)

    Abstr.: Modified Vaccinia Ankara (MVA) was recently approved as a smallpox vaccine. Variola is transmitted by respiratory droplets and MVA immunization by skin scarification (s.s.) protected mice far more effectively against lethal respiratory challenge with vaccinia virus (VACV) than any other route of delivery, and at lower doses. Comparisons of s.s. with intradermal, s.c., or i.m. routes showed that MVAOVA s.s.-generated T cells were both more abundant and transcriptionally unique. MVAOVA s.s. produced greater nos. of lung Ova-specific CD8+ TRM and was superior in protecting mice against lethal VACVOVA respiratory challenge. Nearly as many lung TRM were generated with MVAOVA s.s. immunization compared to intra-tracheal immunization with MVAOVA and both routes vaccination protected mice against lethal pulmonary challenge with VACVOVA. Strikingly, MVAOVA s.s.-generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via intra-tracheal immunization. Overall, our data suggest that heterologous MVA vectors immunized via s.s. are uniquely well-suited as vaccine vectors for respiratory pathogens, which may be relevant to COVID-19. In addn., MVA delivered via s.s. could represent a more ED-sparing smallpox vaccine.

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    Sun, C.; Zhang, L.; Zhang, M.; Liu, Y.; Zhong, M.; Ma, X.; Chen, L. Induction of balance and breadth in the immune response is beneficial for the control of SIVmac239 replication in rhesus monkeys. J. Infect. 2010, 60 (5), 371– 381,  DOI: 10.1016/j.jinf.2010.03.005

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    Induction of balance and breadth in the immune response is beneficial for the control of SIVmac239 replication in rhesus monkeys

    Sun Caijun; Zhang Lei; Zhang Maochao; Liu Yichu; Zhong Miao; Ma Xin; Chen Ling

    The Journal of infection (2010), 60 (5), 371-81 ISSN:.

    OBJECTIVES: The aim of this study was to induce cellular and humoral responses with enhanced breadth and more balanced magnitude as a possible approach for an effective HIV vaccine. METHODS: All nine of the SIVmac239 genes (gag, pol, env, nef, vif, vpx, vpr, rev and tat) were optimized for mammalian expression, synthesized and cloned into recombinant adenovirus type 5 (Ad5). These vectors were used as a vaccine regimen, and the immunogenicity and immune protection of this regimen was assessed in murine and macaques. RESULTS: A vaccine regimen including all nine genes of the SIVmac239 virus was developed, and it was demonstrated that in contrast to single antigen vaccination, the total SIV antigen regimen more effectively elicited the balanced and broad immune responses in murine and macaques. Moreover, the responses afforded effective immune control against infection and replication of the highly pathogenic SIVmac239. CONCLUSIONS: Induction of balance and breadth in the immune response is beneficial in controlling SIVmac239 replication in rhesus monkeys. This study provides insight for the future development of an effective HIV vaccine.

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    Sun, Y.; Chen, M. L.; Yang, D.; Qin, W. B.; Quan, G. L.; Wu, C. B.; Pan, X. Self-assembly nanomicelle-microneedle patches with enhanced tumor penetration for superior chemo-photothermal therapy. Nano Res. 2022, 15 (3), 2335– 2346,  DOI: 10.1007/s12274-021-3817-x

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    Self-assembly nanomicelle-microneedle patches with enhanced tumor penetration for superior chemo-photothermal therapy

    Sun, Ying; Chen, Minglong; Yang, Dan; Qin, Wanbing; Quan, Guilan; Wu, Chuanbin; Pan, Xin

    Nano Research (2022), 15 (3), 2335-2346CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)

    Nanomedicine with high specificity has been a promising tool for cancer diagnosis and therapy. However, the successful application of nanoparticle-based superficial cancer therapy is severely hindered by restricted deep tumor tissue accumulation and penetration. Herein, a self-assembly nanomicelle dissolving microneedle (DMN) patch according to the ''nano in micro'' strategy was conducted to co-deliver a first-line chemotherapeutic agent paclitaxel (PTX), and a photosensitizer IR780 (PTX/IR780-NMs @DMNs) for chemo-photothermal synergetic melanoma therapy. Upon direct insertion into the tumor site, DMNs created a regular and multipoint three-dimensional drug depot to maximize the tumor accumulation. Accompanied by the DMN dissoln., the compn. of the needle matrixes self-assembled into nanomicelles, which could efficiently penetrate deep tumor tissue. Upon laser irradn., the nanomicelles could not only ablate tumor cells directly by photothermal conversion but also trigger PTX release to induce tumor cell apoptosis. In vivo results showed that compared with i.v. injection, IR780 delivered by PTX/IR780-NMs @DMNs was almost completely accumulated at the tumor site. The antitumor results revealed that the PTX/IR780-NMs @DMNs could effectively eliminate tumors with an 88% curable rate without any damage to normal tissues. This work provides a versatile and generalizable framework for designing self-assembly DMN-mediated combination therapy to fight against superficial cancer.

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    Lin, S. Q.; Quan, G. L.; Hou, A. L.; Yang, P. P.; Peng, T. T.; Gu, Y. K.; Qin, W. B.; Liu, R. B.; Ma, X. Y.; Pan, X.; Liu, H.; Wang, L. L.; Wu, C. B. Strategy for hypertrophic scar therapy: Improved delivery of triamcinolone acetonide using mechanically robust tip-concentrated dissolving microneedle array. J. Controlled Release 2019, 306, 69– 82,  DOI: 10.1016/j.jconrel.2019.05.038

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    Strategy for hypertrophic scar therapy: Improved delivery of triamcinolone acetonide using mechanically robust tip-concentrated dissolving microneedle array

    Lin, Shiqi; Quan, Guilan; Hou, Ailin; Yang, Peipei; Peng, Tingting; Gu, Yukun; Qin, Wanbing; Liu, Rongben; Ma, Xiangyu; Pan, Xin; Liu, Hu; Wang, Lili; Wu, Chuanbin

    Journal of Controlled Release (2019), 306 (), 69-82CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

    The purpose of this study was to provide an alternative treatment for HS by establishing a novel intradermal delivery system with a dissolving microneedle array (DMNA). To produce needles of higher mech. strength for successful insertion into the compact and hard HS tissue, hydroxypropyl-B-cyclodextrin (HP-B-CD) was added into sodium hyaluronic acid (HA), the needle material. The hydrogen interaction between HP-B-CD and HA restricted the mobility of the mol. chains, and subsequently increased the elastic modulus of the complex materials. The HP-B-CD also contributed to improved loading of the hydrophobic drug mols. into the DMNA needle tips. To assess the delivery of TA to the HS site via DMNA, an HS model was established in the ventral skin of New Zealand rabbits' ears. It was found that the value of the scar elevation index was decreased to normal, together with the down regulation of mRNA expressions of Collagen I and transforming growth factor-B1 (TGF-B1) following the administration of DMNA contg. TA (TA-DMNA). Western blotting results also revealed decreased protein expressions of both Collagen I and TGF-B1. Hence, TA-DMNA appears to be a promising alternative to multi-injection of TA injection, providing a convenient and low-pain therapeutic strategy for HS treatment.

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    Li, M.; Chen, J.; Liu, Y.; Zhao, J.; Li, Y.; Hu, Y.; Chen, Y. Q.; Sun, L.; Shu, Y.; Feng, F.; Sun, C. Rational design of AAVrh10-vectored ACE2 functional domain to broadly block the cell entry of SARS-CoV-2 variants. Antiviral Res. 2022, 205, 105383  DOI: 10.1016/j.antiviral.2022.105383

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    Rational design of AAVrh10-vectored ACE2 functional domain to broadly block the cell entry of SARS-CoV-2 variants

    Li, Minchao; Chen, Jiaoshan; Liu, Yajie; Zhao, Jin; Li, Yanjun; Hu, Yunqi; Chen, Yao-qing; Sun, Litao; Shu, Yuelong; Feng, Fengling; Sun, Caijun

    Antiviral Research (2022), 205 (), 105383CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)

    The frequently emerging SARS-CoV-2 variants have weakened the effectiveness of existing COVID-19 vaccines and neutralizing antibody therapy. Nevertheless, the infections of SARS-CoV-2 variants still depend on angiotensin-converting enzyme 2 (ACE2) receptor-mediated cell entry, and thus the sol. human ACE2 (shACE2) is a potential decoy for broadly blocking SARS-CoV-2 variants. In this study, we firstly generated the recombinant AAVrh10-vectored shACE2 constructs, a kind of adeno-assocd. virus (AAV) serotype with pulmonary tissue tropism, and then validated its inhibition capacity against SARS-CoV-2 infection. To further optimize the minimized ACE2 functional domain candidates, a comprehensive anal. was performed to clarify the interactions between the ACE2 orthologs from various species and the receptor binding domain (RBD) of SARS-CoV-2 spike (S) protein. Based on the key interface amino acids, we designed a series of truncated ACE2 orthologs, and then assessed their potential affinity to bind to SARS-CoV-2 variants RBD in silico. Of note, we found that the 24-83aa fragment of dog ACE2 (dACE224-83) had a higher affinity to the RBD of SARS-CoV-2 variants than that of human ACE2. Importantly, AAVrh10-vectored shACE2 or dACE224-83 constructs exhibited a broadly blockage breadth against SARS-CoV-2 prototype and variants in vitro and ex vivo. Collectively, these data highlighted a promising therapeutic strategy against SARS-CoV-2 variants.

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    Luo, H.; Jia, T.; Chen, J.; Zeng, S.; Qiu, Z.; Wu, S.; Li, X.; Lei, Y.; Wang, X.; Wu, W.; Zhang, R.; Zou, X.; Feng, T.; Ding, R.; Zhang, Y.; Chen, Y. Q.; Sun, C.; Wang, T.; Fang, S.; Shu, Y. The Characterization of Disease Severity Associated IgG Subclasses Response in COVID-19 Patients. Front. Immunol. 2021, 12, 632814  DOI: 10.3389/fimmu.2021.632814

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    The characterization of disease severity associated IgG subclasses response in COVID-19 patients

    Luo, Huanle; Jia, Tingting; Chen, Jiamin; Zeng, Shike; Qiu, Zengzhao; Wu, Shu; Li, Xu; Lei, Yuxuan; Wang, Xin; Wu, Weihua; Zhang, Renli; Zou, Xuan; Feng, Tiejian; Ding, Ruxia; Zhang, Yue; Chen, Yao-Qing; Sun, Caijun; Wang, Tian; Fang, Shisong; Shu, Yuelong

    Frontiers in Immunology (2021), 12 (), 632814CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)

    Increasing evidence suggests that dysregulated immune responses are assocd. with the clin. outcome of coronavirus disease 2019 (COVID-19). Nucleocapsid protein (NP)-, spike (S)-, receptor binding domain (RBD)- specific Ig isotypes, IgG subclasses and neutralizing antibody (NAb) were analyzed in 123 serum from 63 hospitalized patients with severe, moderate, mild or asymptomatic COVID-19. Mild to modest correlations were found between disease severity and antigen specific IgG subclasses in serum, of which IgG1 and IgG3 were neg. assocd. with viral load in nasopharyngeal swab. Multiple cytokines were significantly related with antigen-specific Ig isotypes and IgG subclasses, and IL-1β was pos. correlated with most antibodies. Furthermore, the old patients (≤ 60 years old) had higher levels of chemokines, increased NAb activities and SARS-CoV-2 specific IgG1, and IgG3 responses and compromised T cell responses compared to the young patients (≤ 18 years old), which are related with more severe cases. Higher IgG1 and IgG3 were found in COVID-19 patients with comorbidities while biol. sex had no effect on IgG subclasses. Overall, the authors have identified diseases severity was related to higher antibodies, of which IgG subclasses had weakly neg. correlation with viral load, and cytokines were significantly assocd. with antibody response. Further, advancing age and comorbidities had obvious effect on IgG1 and IgG3.

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    Li, P.; Wang, Q.; He, Y.; Yang, C.; Zhang, Z.; Liu, Z.; Liu, B.; Yin, L.; Cui, Y.; Hu, P.; Liu, Y.; Zheng, P.; Wang, W.; Qu, L.; Sun, C.; Guan, S.; Feng, L.; Chen, L. Booster vaccination is required to elicit and maintain COVID-19 vaccine-induced immunity in SIV-infected macaques. Emerg. Microbes Infect. 2023, 12 (1), e2136538  DOI: 10.1080/22221751.2022.2136538

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    Booster vaccination is required to elicit and maintain COVID-19 vaccine-induced immunity in SIV-infected macaques

    Li, Pingchao; Wang, Qian; He, Yizi; Yang, Chenchen; Zhang, Zhengyuan; Liu, Zijian; Liu, Bo; Yin, Li; Cui, Yilan; Hu, Peiyu; Liu, Yichu; Zheng, Pingqian; Wang, Wei; Qu, Linbing; Sun, Caijun; Guan, Suhua; Feng, Liqiang; Chen, Ling

    Emerging Microbes & Infections (2023), 12 (1), e2136538/1-e2136538/13CODEN: EMIMC4; ISSN:2222-1751. (Taylor & Francis Ltd.)

    Prolonged infection and possible evolution of SARS-CoV-2 in patients living with uncontrolled HIV-1 infection highlight the importance of an effective vaccination regimen, yet the immunogenicity of COVID-19 vaccines and predictive immune biomarkers have not been well investigated. Herein, we report that the magnitude and persistence of antibody and cell-mediated immunity (CMI) elicited by an Ad5-vectored COVID-19 vaccine are impaired in SIV-infected macaques with high viral loads (> 105 genome copies per mL plasma, SIVhi) but not in macaques with low viral loads (< 105, SIVlow). After a second vaccination, the immune responses are robustly enhanced in all uninfected and SIVlow macaques. These responses also show a moderate increase in 70% SIVhi macaques but decline sharply soon after. Further anal. reveals that decreased antibody and CMI responses are assocd. with reduced circulating follicular helper T cell (TFH) counts and aberrant CD4/CD8 ratios, resp., indicating that dysregulation of CD4+ T cells by SIV infection impairs the COVID-19 vaccine-induced immunity. Ad5-vectored COVID-19 vaccine shows no impact on SIV loads or SIV-specific CMI responses. Our study underscores the necessity of frequent booster vaccinations in HIV-infected patients and provides indicative biomarkers for predicting vaccination effectiveness in these patients.

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    Wen, Z.; Fang, C.; Liu, X.; Liu, Y.; Li, M.; Yuan, Y.; Han, Z.; Wang, C.; Zhang, T.; Sun, C. A recombinant Mycobacterium smegmatis-based surface display system for developing the T cell-based COVID-19 vaccine. Hum. Vaccines Immunother. 2023, 19 (1), 2171233  DOI: 10.1080/21645515.2023.2171233

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    A recombinant Mycobacterium smegmatis-based surface display system for developing the T cell-based COVID-19 vaccine

    Wen, Ziyu; Fang, Cuiting; Liu, Xinglai; Liu, Yan; Li, Minchao; Yuan, Yue; Han, Zirong; Wang, Congcong; Zhang, Tianyu; Sun, Caijun

    Human Vaccines & Immunotherapeutics (2023), 19 (1), 2171233/1-2171233/12CODEN: HVIUAK; ISSN:2164-554X. (Taylor & Francis Ltd.)

    The immune escape mutations of SARS-CoV-2 variants emerged frequently, posing a new challenge to weaken the protective efficacy of current vaccines. Thus, the development of novel SARS-CoV-2 vaccines is of great significance for future epidemic prevention and control. We herein reported constructing the attenuated Mycobacterium smegmatis (M. smegmatis) as a bacterial surface display system to carry the spike (S) and nucleocapsid (N) of SARS-CoV-2. To mimic the native localization on the surface of viral particles, the S or N antigen was fused with truncated PE_PGRS33 protein, which is a transportation component onto the cell wall of Mycobacterium tuberculosis (M.tb). The sub-cellular fraction anal. demonstrated that S or N protein was exactly expressed onto the surface (cell wall) of the recombinant M. smegmatis. After the immunization of the M. smegmatis-based COVID-19 vaccine candidate in mice, S or N antigen-specific T cell immune responses were effectively elicited, and the subsets of central memory CD4+ T cells and CD8+ T cells were significantly induced. Further anal. showed that there were some potential cross-reactive CTL epitopes between SARS-CoV-2 and M.smegmatis. Overall, our data provided insights that M. smegmatis-based bacterial surface display system could be a suitable vector for developing T cell-based vaccines against SARS-CoV-2 and other infectious diseases.

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