丽水市十三项呼吸道病原体感染情况及特点分析北大核心CSCD

目的了解丽水市呼吸道病原体感染情况及流行病学特征,为呼吸道传染病诊疗与防控提供科学依据。方法回顾性分析2020年3月至2021年12月丽水市人民医院收治的4035例呼吸道感染患者13项呼吸道病原体PCR毛细电泳核酸检测结果,并分析病原体感染分布特征。结果呼吸道病原体感染患者阳性检出率为32.24%(1301/4035),检出率前5位分别是HRV(16.60%)、HRSV(7.09%)、HPIV(2.87%)、HMPV(2.21%)、HADV(1.96%)。混合感染阳性占比为7.61%(99/1301),Boca病毒(76.0%)与Ch(46.15%)易与其它病原体形成混合感染。不同性别呼吸道病原体感染率差异无统计学意义(P>0.05)。虽然不同季节呼吸道病原体整体感染率差异无统计学意义(P>0.05),但HRV好发于春秋两季,而HPIV在春秋两季感染率较低,春季HRSV感染率较低,HADV在夏秋两季感染率较低,HMPV在冬季较为流行。未成年人呼吸道病原体感染率较高,HRSV、HRV、HPIV、HADV和Boca主要发生于未成年人组,InfB和HMPV在未成年和青年人群感染率都较高。结论未成年人群是呼吸道病原体易感人群,应加强未成年人呼吸道传染病防控。     

乌鲁木齐地区RT-PCR法检测儿童急性呼吸道病毒的临床研究

目的利用多重荧光逆转录聚合酶链反应(RT-PCR)分析急性下呼吸道感染患儿4种病毒:人腺病毒(HADV)、人博卡病毒(HBoV)、人偏肺病毒(HMPV)、人呼吸道合胞病毒(HRSV)的感染情况。方法收集1045例急性呼吸道感染的住院患儿鼻咽深部分泌物标本,采用多重荧光RT-PCR进行呼吸道病毒4项指标检测,就病毒分布情况、季节因素等方面进行临床流行病学特点分析。结果1045例患儿中有281例4种呼吸道病毒阳性,总阳性率为26.89%;其中单一病毒感染194例(69.04%)、混合病毒感染87例(30.96%),HMPV感染最多,为120例(42.70%)、其次为HRSV感染119例(42.35%);在各年龄组中≤3岁组阳性229例(36.06%),4~7岁组阳性114例(42.22%),≥8岁组阳性63例(45.00%)。从季节分布来看,春、夏、秋、冬四季的检出率分别为25.68%、28.24%、49.34%、65.57%。结论多重荧光RT-PCR法能快速检测乌鲁木齐地区儿童急性呼吸道病毒,呼吸道病毒感染主要为HMPV和HRSV感染;呼吸道病毒患儿感染率最高年龄段为≥8岁;以秋季和冬季为呼吸道病毒感染高发期。     

Progress in respiratory virus vaccine development

Viral respiratory infections cause significant morbidity and mortality in infants and young children as well as in at-risk adults and the elderly. Although many viral pathogens are capable of causing respiratory disease, vaccine development has to focus on a limited number of pathogens, such as those that commonly cause serious lower respiratory illness (LRI). Whereas influenza virus vaccines have been available for some time (see the review by Clark and Lynch in this issue), vaccines against other medically important viruses such as respiratory syncytial virus (RSV), the parainfluenza viruses (PIVs), and metapneumovirus (MPVs) are not available. This review aims to provide a brief update on investigational vaccines against RSV, the PIVs, and MPV that have been evaluated in clinical trials or are currently in clinical development.     

埃博拉疫苗临床试验研究进展

埃博拉病毒病以往被人们称作埃博拉病毒性出血热,目前尚无针对该病的特异性治疗措施与药物,疫苗成为最有可能预防控制病毒传播的手段。目前,多种埃博拉候选疫苗已经进入了临床试验,包括减毒水疱性口炎病毒载体埃博拉疫苗(rVSV-ZEBOV)、复制缺陷型黑猩猩3型腺病毒载体埃博拉疫苗(cAd3-EBO或ChAd3-EBO-Z)、复制缺陷型人5型腺病毒载体埃博拉疫苗(Ad5-EBOV)和人3型副流感病毒载体埃博拉疫苗(HPIV3)等。ChAd3-EBO-Z和Ad5-EBOV等在早期的临床试验中均表现出较好的安全性和免疫原性。rVSV-ZEBOV率先完成了Ⅲ期临床试验,已证实其对埃博拉病毒病的预防具有很高的保护效力,但是研究数据也提示了该疫苗可能存在的安全性问题。本文旨在回顾2014年以来埃博拉疫苗在临床试验研究方面的重大进展,讨论尚存的问题和挑战以及未来的发展方向。     

Viral respiratory tract infections among patients with acute undifferentiated fever in Vietnam

To investigate the proportion of viral respiratory tract infections among acute undifferentiated fevers (AUFs) at primary health facilities in southern Vietnam during 2001-2005, patients with AUF not caused by malaria were enrolled at twelve primary health facilities and a clinic for malaria control program. Serum was collected on first presentation (t0) and after 3 weeks (t3) for serology. After exclusion of acute dengue infection, acute and convalescent serum samples from 606 patients were using enzyme-linked immunoassays to detect IgA, as well as IgM and IgG antibodies against common respiratory viruses. Paired sera showed the following infections: human parainfluenza virus (HPIV, 4.7%), influenza B virus (FLUBV, 2.2%), influenza A virus (FLUAV, 1.9%) and human respiratory syncytial virus (HRSV, 0.6%). There was no association between type of infection and age, sex or seasonality; some inter-annual differences were observed for influenza. Antibody prevalence, indicative of previous infections, was relatively low: HPV, 56.8%, FLUBV, 12.1%; FLUAV, 5.9% and HRSV, 6.8%.     

A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters

Single-dose vaccines with the ability to restrict SARS-CoV-2 replication in the respiratory tract are needed for all age groups, aiding efforts toward control of COVID-19. We developed a live intranasal vector vaccine for infants and children against COVID-19 based on replication-competent chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) that express the native (S) or prefusion-stabilized (S-2P) SARS-CoV-2 S spike protein, the major protective and neutralization antigen of SARS-CoV-2. B/HPIV3/S and B/HPIV3/S-2P replicated as efficiently as B/HPIV3 in vitro and stably expressed SARS-CoV-2 S. Prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P induced significantly higher titers compared to B/HPIV3/S of serum SARS-CoV-2–neutralizing antibodies (12-fold higher), serum IgA and IgG to SARS-CoV-2 S protein (5-fold and 13-fold), and IgG to the receptor binding domain (10-fold). Antibodies exhibited broad neutralizing activity against SARS-CoV-2 of lineages A, B.1.1.7, and B.1.351. Four weeks after immunization, hamsters were challenged intranasally with 10^4.5 50% tissue-culture infectious-dose (TCID₅₀) of SARS-CoV-2. In B/HPIV3 empty vector-immunized hamsters, SARS-CoV-2 replicated to mean titers of 10^6.6 TCID₅₀/g in lungs and 10⁷ TCID₅₀/g in nasal tissues and induced moderate weight loss. In B/HPIV3/S-immunized hamsters, SARS-CoV-2 challenge virus was reduced 20-fold in nasal tissues and undetectable in lungs. In B/HPIV3/S-2P–immunized hamsters, infectious challenge virus was undetectable in nasal tissues and lungs; B/HPIV3/S and B/HPIV3/S-2P completely protected against weight loss after SARS-CoV-2 challenge. B/HPIV3/S-2P is a promising vaccine candidate to protect infants and young children against HPIV3 and SARS-CoV-2.

The betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 and rapidly spread globally (1). In the first year of the pandemic, over 105 million infections and 2.3 million deaths have been reported worldwide, including over 27 million cases and 500,000 deaths in the United States (https://covid19.who.int/). Vaccines are being rapidly deployed in a race to control ongoing infections and the emergence of variants of concern (2), with increased virulence and altered antigenicity.SARS-CoV-2 infects and spreads primarily via the respiratory route (3, 4), and mucosal surfaces of the respiratory tract represent the primary site of infection. COVID-19, the disease caused by SARS-CoV-2, is characterized by upper and lower respiratory tract symptoms, fever, chills, body aches, and fatigue, and in some cases gastrointestinal and other symptoms with involvement of additional tissues (5, 6).SARS-CoV-2 infection is initiated by the spike (S) surface glycoprotein, the main target for SARS-CoV-2–neutralizing antibodies. The S protein is a trimeric class I fusion glycoprotein. Each protomer consists of two functionally distinct subunits, S1 and S2, linked by a furin cleavage site; S2 contains an additional proteolytic cleavage site S2′. S2/S2′ cleavage is mediated by the transmembrane protease serine 2 (TMPRSS2) (1, 7–9). The S1 subunit contains the receptor-binding domain (RBD). The S2 subunit contains the membrane fusion machinery, including the hydrophobic fusion peptide and α-helical heptad repeats (7, 9).Binding of the S RBD to its receptor, human angiotensin converting enzyme 2, triggers a change, from the closed and metastable prefusion conformation to the open and stable postfusion form that drives membrane fusion enabling viral entry (1). Stabilization of the S protein in its native prefusion state should preserve antibody epitopes, including immunodominant sites of the RBD, required to elicit high-quality neutralizing antibody responses (9–13). Thus, a prefusion-stabilized version of the S protein is the optimal vaccine immunogen (13–15).Vaccines for SARS-CoV-2 are available, but currently are limited to individuals 12 y of age or older. They are administered intramuscularly, which does not directly stimulate mucosal immunity in the respiratory tract, the primary site of SARS-CoV-2 infection and shedding. While the major burden of COVID-19 disease is in adults, infection and disease also occurs in infants and young children, contributing to viral transmission. Therefore, the development of safe and effective pediatric COVID-19 vaccines is critical for worldwide control of COVID-19. The ideal vaccine should be effective at a single dose, inducing durable and broad systemic immunity, as well as T and B cell respiratory mucosal immunity that completely blocks SARS-CoV-2 infection and transmission.Here we describe a vectored SARS-CoV-2 vaccine candidate for intranasal immunization of infants and young children. The vaccine is based on an attenuated, replication-competent parainfluenza virus type 3 (PIV3) vector called B/HPIV3 (16) expressing the SARS-CoV-2 S protein. B/HPIV3 consists of bovine PIV3 (BPIV3) strain Kansas in which the BPIV3 hemagglutinin-neuraminidase (HN) and fusion (F) glycoproteins (the two PIV3 neutralization antigens) have been replaced by those of human PIV3 strain JS (16, 17). The BPIV3 backbone provides host range restriction of replication in humans, serving as the basis for strong and stable attenuation (17, 18). B/HPIV3 originally was developed as a live vaccine candidate against HPIV3, and was well-tolerated in young children (17). Moreover, B/HPIV3 has been used to express the F glycoprotein of another human respiratory pathogen, human respiratory syncytial virus (HRSV), as a bivalent HPIV3/HRSV vaccine candidate. This vaccine candidate was well-tolerated in children >2 mo of age (18) (Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00686075","term_id":"NCT00686075"}}NCT00686075), and optimized versions are in further clinical development as pediatric vaccines (19, 20). In the present study, we used B/HPIV3 to express wild-type (S) or prefusion-stabilized (S-2P) versions of the SARS-CoV-2 S protein, creating the vaccine candidates B/HPIV3/S and B/HPIV3/S-2P. These were evaluated in vitro and in hamsters as live-attenuated SARS-CoV-2 intranasal vaccine candidates.     

Progress in respiratory virus vaccine development

Viral respiratory infections continue to cause significant morbidity and mortality in infants and young children as well as in at-risk adults and the elderly. Although many viral pathogens are capable of causing acute respiratory disease, vaccine development has to focus on a limited number of pathogens (i.e., agents that commonly cause serious lower respiratory disease). Inactivated and, more recently, live attenuated influenza virus vaccines are the mainstay of interpandemic influenza prevention, but vaccines are not available yet for other important viruses such as respiratory syncytial virus, metapneumovirus, the parainfluenza viruses, and avian influenza viruses with pandemic potential. Reverse genetics systems that allow rational vaccine development are now widely used, and considerable progress has been made in preclinical and clinical development of novel respiratory virus vaccines.     

Human Respiratory Syncytial Virus Infection in a Human T Cell Line Is Hampered at Multiple Steps

Human respiratory syncytial virus (HRSV) is the most frequent cause of severe respiratory disease in children. The main targets of HRSV infection are epithelial cells of the respiratory tract, and the great majority of the studies regarding HRSV infection are done in respiratory cells. Recently, the interest on respiratory virus infection of lymphoid cells has been growing, but details of the interaction of HRSV with lymphoid cells remain unknown. Therefore, this study was done to assess the relationship of HRSV with A3.01 cells, a human CD4⁺ T cell line. Using flow cytometry and fluorescent focus assay, we found that A3.01 cells are susceptible but virtually not permissive to HRSV infection. Dequenching experiments revealed that the fusion process of HRSV in A3.01 cells was nearly abolished in comparison to HEp-2 cells, an epithelial cell lineage. Quantification of viral RNA by RT-qPCR showed that the replication of HRSV in A3.01 cells was considerably reduced. Western blot and quantitative flow cytometry analyses demonstrated that the production of HRSV proteins in A3.01 was significantly lower than in HEp-2 cells. Additionally, using fluorescence in situ hybridization, we found that the inclusion body-associated granules (IBAGs) were almost absent in HRSV inclusion bodies in A3.01 cells. We also assessed the intracellular trafficking of HRSV proteins and found that HRSV proteins colocalized partially with the secretory pathway in A3.01 cells, but these HRSV proteins and viral filaments were present only scarcely at the plasma membrane. HRSV infection of A3.01 CD4⁺ T cells is virtually unproductive as compared to HEp-2 cells, as a result of defects at several steps of the viral cycle: Fusion, genome replication, formation of inclusion bodies, recruitment of cellular proteins, virus assembly, and budding.     

Respiratory Syncytial Virus Bronchiolitis

Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract illness in infants and children worldwide and is responsible for over 120 000 annual hospitalizations in infants in the US alone. RSV is also recognized as a major respiratory viral pathogen in the elderly and other high-risk populations. Bronchiolitis, pneumonia, apnea, respiratory failure, and death are well known manifestations of severe acute RSV disease. RSV infection has also been associated with recurrent wheezing in children, but the mechanisms involved in this association are not completely understood. The host immune response plays a significant role in controlling the infection but is likely also involved in augmenting the disease through pathways that have not been completely identified. The treatment options for RSV infection are very limited. Ribavirin, corticosteroids, and bronchodilators are not used routinely because they have not proven to be sufficiently effective. Education of caregivers, strict handwashing, and avoidance of exposure to environmental factors associated with severe forms of RSV infection are among the most effective preventive means. Passive immunization with monoclonal antibodies provides protection against severe RSV disease in high-risk children. Clinical trials to evaluate the safety and efficacy of a second-generation monoclonal antibody are underway. Efforts to develop a safe and effective RSV vaccine have continued despite the poor outcomes observed following the administration of formalin-inactivated formulations in the 1960s. In the last decade, live attenuated vaccines (including those developed by recombinant techniques) and purified subunit vaccines have all been evaluated in humans. Results of clinical trials have been encouraging, but the availability of a safe and effective RSV vaccine is not a reality yet. Better prevention strategies will have an impact, not only on acute morbidity caused by RSV, but will also likely have an effect on ameliorating the chronic consequences of this disease.     

Modified Vaccinia Virus Ankara (MVA) as Production Platform for Vaccines against Influenza and Other Viral Respiratory Diseases

Respiratory viruses infections caused by influenza viruses, human parainfluenza virus (hPIV), respiratory syncytial virus (RSV) and coronaviruses are an eminent threat for public health. Currently, there are no licensed vaccines available for hPIV, RSV and coronaviruses, and the available seasonal influenza vaccines have considerable limitations. With regard to pandemic preparedness, it is important that procedures are in place to respond rapidly and produce tailor made vaccines against these respiratory viruses on short notice. Moreover, especially for influenza there is great need for the development of a universal vaccine that induces broad protective immunity against influenza viruses of various subtypes. Modified Vaccinia Virus Ankara (MVA) is a replication-deficient viral vector that holds great promise as a vaccine platform. MVA can encode one or more foreign antigens and thus functions as a multivalent vaccine. The vector can be used at biosafety level 1, has intrinsic adjuvant capacities and induces humoral and cellular immune responses. However, there are some practical and regulatory issues that need to be addressed in order to develop MVA-based vaccines on short notice at the verge of a pandemic. In this review, we discuss promising novel influenza virus vaccine targets and the use of MVA for vaccine development against various respiratory viruses.     

Structural characterization of the human respiratory syncytial virus fusion protein core

Human respiratory syncytial virus (HRSV) is a major cause of a number of severe respiratory diseases, including bronchiolitis and pneumonia, in infants and young children. The HRSV F protein, a glycoprotein essential for viral entry, is a primary target for vaccine and drug development. Two heptad-repeat regions within the HRSV F sequence were predicted by the computer program learncoil-vmf. These regions are thought to form trimer-of-hairpins-like structures, similar to those found in the fusion proteins of several enveloped viruses. The hairpin structure likely brings the viral and cellular membranes into close apposition, thereby facilitating membrane fusion and subsequent viral entry. Here, we show that peptides, denoted HR-N and HR-C, corresponding to the heptad-repeat regions from the N-terminal and C-terminal segments of the HRSV F protein, respectively, form a stable alpha-helical trimer of heterodimers. The HRSV N/C complex was crystallized and its x-ray structure was determined at 2.3-A resolution. As anticipated, the complex is a six-helix bundle in which the HR-N peptides form a three-stranded, central coiled coil, and the HR-C peptides pack in an antiparallel manner into hydrophobic grooves on the coiled-coil surface. There is remarkable structural similarity between the HRSV N/C complex and the fusion protein core of other viruses, including HIV-1 gp41. In addition, earlier work has shown that HRSV HR-C peptides, like the HIV-1 gp41 C peptides, inhibit viral infection. Thus, drug discovery and vaccine development strategies aimed at inhibiting viral entry by blocking hairpin formation may be applied to the inhibition of HRSV.     

Tuberculosis vaccines: Opportunities and challenges

Tuberculosis (TB) is a serious disease around the world. Bacillus Calmette–Guérin (BCG) is the only TB vaccine licensed for use in human beings, and is effective in protecting infants and children against severe miliary and meningeal TB. However, BCG's protective efficacy is variable in adults. Novel TB vaccine candidates being developed include whole‐cell vaccines (recombinant BCG (rBCG), attenuated Mycobacterium tuberculosis , killed M. tuberculosis or Mycobacterium vaccae ), adjuvanted protein subunit vaccines, viral vector‐delivered subunit vaccines, plasmid DNA vaccines, RNA‐based vaccines etc. At least 12 novel TB vaccine candidates are now in clinical trials, including killed M. vaccae , rBCG ΔureC::hly , adjuvanted fusion proteins M72 and H56 and viral vectored MVA85A. Unfortunately, in TB, there are no correlates of vaccine‐induced protection, although cell‐mediated immune responses such as interferon‐gamma (IFN‐γ) production are widely used to assess vaccine's immunogenicity. Recent studies suggested that central memory T cells and local secreted IgA correlated with protection against TB disease. Clinical TB vaccine efficacy trials should invest in identifying correlates of protection, and evaluate new TB biomarkers emerging from human and animal studies. Accumulating new knowledge on M. tuberculosis antigens and immune profiles correlating with protection or disease risk will be of great help in designing next generation of TB vaccines.     

Update on the development and use of viral and bacterial vaccines for the prevention of acute otitis media.

Acute otitis media (AOM) is the most frequent diagnosis in physician offices among children 1-4 years of age. Viruses that cause upper respiratory tract infections (i.e., respiratory syncytial virus [RSV], influenza virus, parainfluenza virus [PIV], and others) play an important role in the development of AOM. Prevention of infections with these viral pathogens likely would reduce the incidence of AOM. In three previous studies, influenza virus vaccines showed 30-36% efficacy against the development of AOM. Vaccines to prevent infections with RSV and PIV type 3 are undergoing clinical testing at this time. The three major bacterial pathogens causing AOM are Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis. Pneumococcal conjugate vaccine, licensed in the United States in 2000, was shown in two pivotal trials to reduce the incidence of all causes of AOM by 6%, pneumococcal AOM by 34%, and pneumococcal AOM caused by serotypes contained in the vaccine by 57%. Currently, vaccines against NTHi and M. catarrhalis are under development.     

More antibody with less antigen: can immunogenicity of attenuated live virus vaccines be improved?

New or improved vaccines against viruses such as influenza, parainfluenza types 1-3, measles, dengue, and respiratory syncytial virus would prevent an enormous burden of morbidity and mortality. Vaccines or vaccine candidates exist against these viral diseases, but all could potentially be improved if the immunogenicity of the vaccine could be enhanced. We found that the immunogenicity in primates of a live-attenuated vaccine candidate for parainfluenza virus type 3, an enveloped RNA virus that is an important etiologic agent of pediatric respiratory tract disease, could be enhanced by expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) from an extra gene inserted into the genome of a cDNA-derived virus. Expression of GM-CSF by the live attenuated recombinant virus did not per se affect the level of pulmonary viral replication in rhesus monkeys after topical administration, which was 40-fold lower than that of WT parainfluenza virus type 3. Despite that, the expressed extra gene augmented the virus-specific serum antibody response to a level that was (i) 3- to 6-fold higher than that induced by the same virus with an unrelated RNA insert of equal length and (ii) equal to the response induced by nonattenuated WT virus. In addition, topical immunization with the attenuated virus expressing GM-CSF induced a greater number of virus-specific IFN-gamma-secreting T lymphocytes in the peripheral blood of monkeys than did immunization with the control virus bearing an unrelated RNA insert. These findings show that the immunogenicity of a live-attenuated vaccine virus in primates can be enhanced without increasing the level of virus replication. Thus, it might be possible to develop live-attenuated vaccines that are as immunogenic as parental WT virus or, possibly, even more so.     

Human parainfluenza virus type 3 (HPIV 3) community-acquired pneumonia (CAP) mimicking pertussis in an adult: the diagnostic importance of hoarseness and monocytosis

Background

There are relatively few causes of acute community-acquired pneumonias (CAPs) in adults associated with prolonged cough. In adults the most common acute CAPs with a prominent and persistent nonproductive cough are due to Mycoplasma pneumoniae, Chlamydophilia (Chlamydia) pneumoniae, or Bordetella pertussis (pertussis). Pertussis is an underrecognized and underappreciated cause of CAP in adults. Different from classic pertussis in children, pertussis in adults presents with prolonged dry cough, that is, the “100-day cough.” In pertussis, the characteristic nonspecific laboratory findings are leukocytosis and relative lymphocytosis. Dry cough accompanied by hoarseness with CAP in an adult should suggest C. pneumoniae or a respiratory virus (eg, influenza, parainfluenza, respiratory syncytial virus).

Methods

We present the case of a young woman who presented with a prominent and persistent pertussis-like cough with hoarseness. She had no leukocytosis or relative lymphopenia, which argued against the diagnosis of pertussis. Notably, she had persistent monocytosis. Her protracted pertussis-like cough that persisted during her hospitalization was so impressive that the diagnostic impression was pertussis. Direct fluorescent antibody (FA) and throat cultures were negative for pertussis. Furthermore, her hoarseness suggested the possibility of C. pneumoniae, but her C. pneumoniae immunoglobulin-M titer was negative.

Results

Because C. pneumoniae was ruled out, her hoarseness suggested a respiratory viral cause. A respiratory FA viral panel and viral throat cultures were obtained. The respiratory FA viral panel was negative for influenza A/B, respiratory syncytial virus, metapneumovirus, adenovirus, cytomegalovirus, and parainfluenza viruses. However, her viral throat cultures grew parainfluenza virus type 3 (HPIV 3), confirming the diagnosis.

Conclusion

To the best of our knowledge, this is the first case of HPIV 3 CAP presenting with a prominent and persistent pertussoid cough in an adult mimicking pertussis with hoarseness and monocytosis.     

狂犬病病毒糖蛋白重组表达及其基因工程疫苗研究进展

狂犬病病毒糖蛋白(RVGP)是唯一暴露于病毒颗粒表面的抗原,能够诱导宿主产生中和抗体,也是唯一存在于所有新型狂犬病疫苗中的病毒成分。本文综述了国内外学者利用原核系统,以及包括酵母系统、植物系统、昆虫细胞系统在内的真核系统和哺乳动物细胞系统、病毒载体系统来表达具有免疫原性的重组狂犬病病毒糖蛋白(rRVGP),并对其与天然RVGP在结构和激发机体免疫反应方面的相似性进行的相关研究,为狂犬病基因工程新型疫苗提供研究思路。     

Development of Novel Vaccines against Enterovirus-71

The hand, foot and mouth disease is caused by a group of Enteroviruses such as Enterovirus 71 (EV-A71) and Coxsackievirus CV-A5, CV-A8, and CV-A16. Mild symptoms of EV-A71 infection in children range from high fever, vomiting, rashes and ulcers in mouth but can produce more severe symptoms such as brainstem and cerebellar encephalitis, leading up to cardiopulmonary failure and death. The lack of vaccines and antiviral drugs against EV-A71 highlights the urgency of developing preventive and treatment agents against EV-A71 to prevent further fatalities. Research groups have developed experimental inactivated vaccines, recombinant Viral Protein 1 (VP1) vaccine and virus-like particles (VLPs). The inactivated EV-A71 vaccine is considered the safest viral vaccine, as there will be no reversion to the infectious wild type strain. The recombinant VP1 vaccine is a cost-effective immunogen, while VLPs contain an arrangement of epitopes that can elicit neutralizing antibodies against the virus. As each type of vaccine has its advantages and disadvantages, increased studies are required in the development of such vaccines, whereby high efficacy, long-lasting immunity, minimal risk to those vaccinated, safe and easy production, low cost, dispensing the need for refrigeration and convenient delivery are the major goals in their design.     

Evaluation of combined live, attenuated respiratory syncytial virus and parainfluenza 3 virus vaccines in infants and young children

We evaluated a combination respiratory syncytial virus (RSV) and parainfluenza 3 virus (PIV3) live, attenuated intranasal vaccine for safety, viral replication, and immunogenicity in doubly seronegative children 6-18 months old. RSV cpts-248/404 and PIV3-cp45 vaccines were combined in a dose of 10(5) plaque-forming units of each per 0.5-mL dose and compared with monovalent vaccines or placebo. The virus shedding pattern of RSV was not different between monovalent RSV cpts-248/404 vaccine and combination vaccine. Modest reductions in the shedding of PIV3-cp45 vaccine virus were found after the administration of RSV cpts-248/404 and PIV3-cp45 vaccine, relative to monovalent PIV3 vaccine; 16 (76%) of 21 children given combination vaccine shed PIV3-cp45 versus 11 (92%) of 12 of those given monovalent PIV3 vaccine. Both vaccines were immunogenic, and antibody responses were similar between the monovalent groups and the combination group. Combined RSV/PV3 vaccine is feasible for simultaneous administration, and further studies are warranted.     

In the era of rapid mRNA-based vaccines: Why is there no effective hepatitis C virus vaccine yet?

Hepatitis C virus(HCV) is responsible for no less than 71 million people chronically infected and is one of the most frequent indications for liver transplanta-tion worldwide. Despite direct-acting antiviral therapies fuel optimism in controlling HCV infections, there are several obstacles regarding treatment accessibility and reinfection continues to remain a possibility. Indeed, the majority of new HCV infections in developed countries occur in people who inject drugs and are more plausible to get reinfected. To achieve global epidemic control of this virus the development of an effective prophylactic or therapeutic vaccine becomes a must.The coronavirus disease 19(COVID-19) pandemic led to auspicious vaccine development against severe acute respiratory syndrome coronavirus-2(SARSCoV-2) virus, which has renewed interest on fighting HCV epidemic with vaccination. The aim of this review is to highlight the current situation of HCV vaccine candidates designed to prevent and/or to reduce HCV infectious cases and their complications. We will emphasize on some of the crossroads encountered during vaccine development against this insidious virus, together with some key aspects of HCV immunology which have, so far, ham-pered the progress in this area. The main focus will be on nucleic acid-based as well as recombinant viral vector-based vaccine candidates as the most novel vaccine approaches, some of which have been recently and successfully employed for SARS-CoV-2 vaccines. Finally, some ideas will be presented on which methods to explore for the design of live-attenuated vaccines against HCV.