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Since specific therapy is limited to only several antiviral agents, prevention of viral infections is crucial to reduce the incidence and mortality of viral diseases. According to the different periods of transplantation, the strategies might be divided to prophylaxis pre-transplantation, during transplantation and post-transplantation. Before transplantation, selection of virus-seronegative stem cell donors for seronegative recipients, and decreasing virus loads in virus-seropositive donors and recipients should be considered. During transplantation, the strategies of conditioning and GVHD prophylaxis should be chosen prudently to minimize the delay of immune reconstitution. After transplantation, prophylaxis should be performed throughout the risk period such as pre-engraftment and GVHD. The incidence of HSV and VZV infections has decreased from 80% to lower than 5% in the recipients of allo-HSCT receiving antiviral prophylaxis throughout the risk period. Preemptive therapy for reactivation of some latent viruses, such as CMV and EBV has been demonstrated to reduce the progression of viral diseases. Vaccination, such as Measles–Mumps–Rubella and VZV vaccine, seems useful to prevent corresponding viral infections. Influenza virus vaccine is suggested to be given to the recipients prior to each influenza season.
Although multiple strategies have been used, the treatment of viral diseases remains rather a challenge because few agents are available and efficacious. In the recipients of allo-HSCT, immunotherapeutic strategies to restore virus-specific immunity, such as reducing immunosuppressants, DLI and ex vivo generation of virus-specific CTL, are now advocated in the treatment of viral diseases. However, reducing immunosuppressants is unfeasible in many patients due to potential risk of GVHD, and DLI is limited by unavailable stem cell donors and the risk of exacerbating GVHD. Of note, these adoptive cellular therapies are only proven efficacious for a few viruses, such as CMV, EBV and adenovirus. Early intervention has a dramatic influence upon survival and may reduce the extent of permanent injury in survivors. For example, in patients with CARVs infections, treatment is more effective if started prior to development of lower respiratory tract infection (LRTI) or respiratory failure. Our data showed that the patients with EBV fever without tissue involvement had better treatment response than those with end-organ diseases or PTLD.
Symptomatic. Some reports indicate oral human immunoglobulin therapy. Specific therapies are not available.
Indication for treatment includes all HBsAg-positive patients. Vaccination and the addition of hepatitis B immune globulin can be considered in this setting.
Antiviral treatment should be started with the beginning of IST. Tenofovir or entecavir are the drugs of choice. The treatment should be continued 1 year after withdrawal of IST, longer in recipients with cGVHD and patients exposed to depleting Ab.
Mumps virus is typically self-limiting with treatment primarily directed towards supportive care including antipyretics and analgesics. Supportive treatment of mumps orchitis includes bed rest, scrotal support, heat and cold packs as well as antipyretics and analgesics. Antibiotics are also commonly prescribed both because it can be difficult to distinguish mumps orchitis from bacterial infection and to prevent superimposed bacterial infection.29, 30
Treatment with mumps intramuscular immunoglobulin has been shown to have no benefit in mumps epidemics, although the immunoglobulin may have some benefit in early infection in a limited number of cases.31, 32 Although intravenous immunoglobulin may reduce some complications of mumps, there is no universal recommendation for its use.7
Historically, various methods to reduce intratesticular pressure, including interferon therapy,33–35 treatment with oxyphenbutazone36 and surgical management including aspiration37, 38 have been described. Results of these treatments have been variable with unclear impact on the development of long-term testicular atrophy and other complications. Accordingly, there is no universal recommendation in favor of these measures and they are not commonly used in clinical practice.13
Hospital admission is not typically indicated for mumps infection except for cases of serious neurologic and other CNS sequelae, other severe complications, or in cases where patients meet standard hospital admission criteria for other conditions, or require aggressive supportive care measures. In practice, hospitalization for mumps is uncommon.28
To establish an etiological factor for a certain malignancy, in particularly, the etiological role of EBV in NPC initiation, we believe the following criteria modified from Koch’s postulates should be fulfilled.
Vaccines are the most effective and economical preventive approach against viral infections, and vaccines against cancer viruses have the potential of reducing the cancer rate. Successes in the development of the HBV and HPV vaccines have demonstrated this concept. The HBV vaccine has been used for about 20 years to prevent viral transmission to newborns and the resulting life-long infections. The effectiveness of the HBV vaccine in reducing liver cancer will be clear 20 years from now. HPV vaccines provide more than 90% protection against persistent HPV infection for up to five years after vaccination.
In order to clarify the etiological role of EBV in NPC, we believe the most convincing evidence should be the decline of the NPC incidence rate in endemic areas by prevention of EBV infection. In the 1980s, it was first reported that the immune response to purified native or recombinant gp350 (previously termed gp340) EBV protein could protect against EBV-induced lymphoma in cottontop tamarins. Later, a vaccinia-delivered gp350 vaccine was reported to protect infants from EBV infection in a clinical trial of 16 months. In recent years, EBV vaccines containing different antigens have been developed and tested in phase I/II clinical trials, but no vaccine has been taken to advanced-stage trials. Although the recombinant gp350 vaccine could reduce 78% incidence of IM, it could not prevent asymptomatic EBV infection. More importantly, no evidence thus far shows that EBV vaccines are effective in protecting animal models from NPC initiation.
No specific antiviral or licensed vaccine is available for a CoV that infects humans, but a range of candidates exist. Even if MERS-CoV infection is rare, transmits poorly, and does not evolve to become a pandemic threat, it serves in a useful role to drive vaccine research of other CoVs, both current and yet to emerge. For cases in healthcare facilities, improving hand hygiene, the use of PPE (gloves, gown, respiratory, and eye protection), and surface cleaning can help disrupt transmission, as can rapid triage of febrile patients with respiratory signs and symptoms. To prevent MERS-CoV infection from dromedary camels, precautions include avoiding contact with camel nasal secretions, cooking camel meat, and pasteurising camel milk until further studies better quantify the risk attached to each of these potential pathways.
Vaccines to prevent CoV disease require both humoral and cellular immunity. Because airway immune responses may be key to preventing the establishment of human MERS-CoV infection, localised deposition of an aerosolised vaccine could prove useful. A number of vaccine platforms and payloads have proceeded although progress has been challenged by the need for animal models that suitably reconstitute human lower respiratory tract disease to show evidence of any preventative effect. Some candidates have progressed to clinical trials. The spike protein and RBD elicit neutralising antibody responses and have been employed as the payload for a number of platforms including DNA vaccines, modified vaccinia virus Ankara, measles virus, and human- and chimpanzee-adenovirus-based vectors. There are also Venezuelan equine encephalitis replicons expressing nucleocapsid, nanoparticles, and structural and non-structural deletion mutants of MERS-CoV.
Vaccination of camels is likely to be the most rapid, least expensive, and best intervention for preventing rare spillovers that then become amplified by humans in healthcare settings. Successes have been reported, but the approach is challenged by the problem that camels are naturally reinfectable with MERS-CoV, even in the presence of a high titre of neutralising antibodies. To date, camel vaccines reduce viral load but do not prevent virus shedding. Human vaccines could target the occupational at-risk groups, which include healthcare, farm, barn, market, and slaughterhouse workers. More widespread application of a MERS vaccine at this time does not seem warranted.
The rarity of seropositive donors, sometimes low antibody titres, and a lack of clinical evidence have made the use of convalescent sera from recovering MERS patients a possibility for treatment, but one with significant limitations. Instead, human monoclonal antibodies targeting the RBD and polyclonal antibodies may provide treatment options for those at risk of severe outcomes. Clinical trials are awaited.
Early control of viral replication is important and administration of interferon (IFN) β1b or a ribavirin and IFN α2b combination within hours initially showed promise. Their practical use in humans is challenging because, if not infected while in a healthcare setting, humans usually present for care with well advanced disease. Combined treatments which reduce viral replication and the host immune response to it are likely to be valuable developments.
A wide range of repurposed or novel potential antivirals including polymerase, nucleotide synthesis and protease inhibitors, and fusion-inhibiting peptides have been investigated. Corticosteroid use is not recommended for acute respiratory distress syndrome. Comparative studies and randomised controlled trials are mostly lacking.
Viral bronchiolitis, mainly caused by RSV infection, remains the leading cause of infant admission to the PICU (54,55). Recent laboratory tools have also confirmed many other viruses to account for bronchiolitis, either as co-infection with RSV or as the only aetiological pathogen. Such viruses are HRV, hMPV, adenovirus, as well as influenza and parainfluenza viruses (56). Even following the anti-RSV post-prophylaxis era, RSV seems to be the most common cause of bronchiolitis in infancy and is responsible for severe clinical manifestations, longer hospitalisation and PICU admissions (57). Severe bronchiolitis is indicated by persistently increased respiratory effort (tachypnoea, nasal flaring, intercostal, subcostal or suprasternal retractions, accessory muscle use and grunting) hypoxaemia, apnoea or acute respiratory failure. Risk factors for severe disease and/or complications of bronchiolitis, even death, are considered to be prematurity (gestational age <37 weeks), age <12 weeks, chronic pulmonary disease, particularly BPD (also known as chronic lung disease), congenital and anatomic defects of the airways, congenital heart disease, immunodeficiency and neurologic disease (58). Though it is a common and old clinical entity, there is a wide variety in clinical practice and the need to clarify each of the therapeutic means has to be done with large, well-designed clinical studies. When it comes to the treatment of critically ill children, there is a paucity of evidence-based guidelines. Fluid replacement, oxygen supplementation and close monitoring are the first steps in the management of the disease. The role of epinephrine and nebulised bronchodilators in combination with systemic corticosteroids is questioned, but can be given on an individualised basis (59). Nebulised hypertonic saline is a new therapeutic agent, which has not been investigated for possible use in the PICU. Although it is recommended, its use remains to be established. Other therapies, such as Heliox, surfactant and ribavirin, are also being examined, with controversial results thus far. As little seems to have been achieved when it comes to treatment, a lot of emphasis has been given to the prevention of the illness. Hygiene measures and education of caregivers, hospital personnel, nurses and doctors on limiting transmission and elimination of the environmental risk factors are strongly recommended in published guidelines (59). Palivizumab prophylaxis is recommended for infants with risk factors, such as chronic illnesses, prematurity and immunodeficiency, as well as other conditions, which are being clarified at the revised published guidelines (59). Since the burden of RSV bronchiolitis is high, research must aim for the development of an anti-RSV vaccine, as well as new antiviral agents.
HPV is responsible for many benign lesions of the airway tract and the genital area in the adult population, as well as for cancer of the larynx and oral cavity, particularly subtypes 16 and 18 (79,80). A recent study (81) also revealed an increased frequency of HPV infections in neonates and children. Otorhinolaryngologists are the specialists, who treat children with HPV-related lesions localised in the oral cavity, the oropharynx and larynx. These lesions are mostly benign. There are four types of HPV-related lesions concerning the upper airway track: i) squamous papilloma, ii) verruca vulgaris, iii) focal epithelial hyperplasia and iv) condyloma acuminatum.
In children, the most common clinical expression of HPV is recurrent respiratory papillomatosis (RRP). It causes hoarseness of the voice and sometimes the lesions can cause obstruction of the upper airway track. In adults, the clinical behaviour differs, as the disease requires fewer surgical excisions than in children. In children, the lesions caused by HPV often need many surgical procedures before they become extinct and quiescent. Inverted papilloma, which is a type of squamous papilloma, is strongly associated with HPV subtypes 6 and 1 and its incidence in children is twice as high compared to adults (82). Fortunately, the majority of these lesions can be surgically removed and provide the young patient with a good prognosis. Microsurgery, transoral laser microsurgery (TLM) and endoscopic endonasal approach (EEA) are some of the most frequent surgical methods of excision. A review of recent studies dealing with HPV lesions in children revealed only a few cases, which have been treated surgically. The most common approach of surgical treatment is using TLM. However, laser treatment can cause several complications, such as stenosis, burns of the airway tract and scars. An alternative to TLM are microdebriders (83). Microdebriders provide a more accurate excision, removing only the affected tissue and preserving the healthy tissue. The preservation of healthy epithelium is very useful, when repeated interventions are needed, particularly in children. When the lesion causes obstruction of the airway tract, a tracheotomy is necessary to keep the airway open. However, it should be avoided and performed only when it is an emergency because of the danger of spreading the disease to the respiratory tract (84). In the future, the association between HPV-related lesions in children and cancerous lesions in adults needs to be considered carefully, revealing the importance of vaccination in children against HPV (85).
It is important not only to manage symptoms in the acute phase of KD but also to prevent the cardiovascular after-effects. There are three essential treatments for KD: 1) intravenous immunoglobulin (IVIG) to obtain an anti-inflammatory effect, 2) aspirin for anti-inflammatory and antiplatelet effects, and 3) management of any complications (eg, meningitis or disseminated intravascular coagulation). IVIG can mitigate inflammation and the coronary artery complications. A dose of 2 g/kg of IVIG in a single infusion has been found to be effective. This therapy should be initiated within the first 10 days of illness.14,15 IVIG has not been demonstrated to be effective if administered after the first 10 days of illness. Furthermore, one report has noted a risk of unfavorable effects with IVIG regarding cardiac sequelae if IVIG is started on day 9 or later.16 In our patient, IVIG was not administered because he was admitted to our hospital on the 13th day of illness.
Aspirin is often administered with IVIG in patients with KD. In the acute phase, the American Heart Association recommends high-dose aspirin (80–100 mg/kg/day) to achieve an anti-inflammatory effect.14 However, it is not clear if a higher dose would be more effective than the lower dose (30–50 mg/kg/day).17 When the patient remains afebrile for 48–72 hours, the aspirin dose is lowered (3–5 mg/kg/day) and maintained to achieve an antiplatelet effect until the patient shows no evidence of coronary changes for 6–8 weeks after onset.14 In addition, regular echocardiographic evaluation should be performed to assess for the possibility of coronary artery aneurysm.
In our patient, 30 mg/kg/day of aspirin was used to achieve an anti-inflammatory effect from day 13 to day 15 of illness to ensure better tolerance to gastrointestinal and other side effects. The dose of aspirin was reduced to 5 mg/kg/day on day 16 of illness. Because the patient developed liver dysfunction as an adverse effect of aspirin on day 5, the treatment was switched to 200 mg/day of cilostazol on day 13.
It is still unclear if the treatment for KD in adults should be the same as in infants, especially with regard to the dose and duration of IVIG and aspirin administration.
Progress towards establishing the effectiveness of a multi-mAb approach compared to single-mAb strategies has recently been reported [97, 98]. In one report, in order to evaluate the therapeutic potential of multiple broadly neutralizing antibodies on established HIV-1 infection, groups of humanized mice were infected with CCR5-tropic HIV-1 isolates (HIV-1YU2). Humanized mice were used in order to minimize production of anti-human antibodies.
Mice were first treated using antibody monotherapy that evaluated five different broadly neutralizing antibodies. These antibodies were selected based on their neutralizing activity as well as the breadth of clades that could effectively be neutralized in vitro. In addition, each mAb targeted different epitopes. The serum half-lives of these mAbs ranged up to 6.3 days. In general, using monotherapy, viremia rebounded after 14–16 days with the concomitant appearance of gp120 mutations that allowed viral escape from mAb selection. Monotherapy therefore selected for viral escapes by mutation of antibody-targeted epitopes. The ability of a trimix and a penta-mix of bnMAbs to alter the course of infection was then evaluated. In contrast to monotherapy and the trimix, all of the pentamix-treated mice remained below baseline viral loads during the entire treatment course. Prolonged control of the infection was observed with the pentamix primarily due to the long serum half-life of the injected antibodies. The efficacy of these antibody-based drugs may be further enhanced with modifications that extend half-life several folds.
Similar experiments in humanized mice and humans where multiple mAbs were evaluated for therapeutic efficacy against established infections did not reveal a significant benefit to the combination bnMAb approach [101–103]. In those experiments, the broadly neutralizing antibodies (b12, 2G12, and 2F5 in mice; 2G12, 2F5, and 4E10 in humans) were less potent than VRC01 or the bnMAbs used in the Klein et. al. study. This difference in potency as well as the inclusion of two additional mAbs to make a penta-mix may account for the different results.
The mutli-mAb approach is similar to the combination therapies involving antiretroviral, antimicrobial, and anticancer agents since circumventing the selective pressure necessarily involves the simultaneous appearance of multiple mutations. Antibody therapy for HIV also offers the advantage of being able to specifically neutralize the virus, and can recruit other components of the immune system resulting in viral clearance from infected cells by eliciting effector functions. Moreover, immune complexes from bnMAbs may augment native immunity and have far longer half-lives than antiretroviral drugs.
At present, there are no drugs available that can target SARS-CoV-2. Therefore, treatment was focused on symptomatic and respiratory support. All the children inhaled interferon and one of the twins was prescribed ribavirin (10–15 mg/kg.d) in addition. Ten (71.4%) adults with pneumonia were treated Lopinaviritonavir (200/50 mg, 2 tablets, bid), interferon and Chinese medicine. The patients with higher infection index (such as CRP, PCT, ESR, SAA, IL-6) were prescript antibiotics for 5–7 days in addition. All the nine children and 14 adult patients recovered in 2–3 weeks and were discharged after two negative nucleic acid tests. Unfortunately, our follow up found that there were five discharged children were admitted again before we submit this article because their stool showed positive result in SARS-CoV-2 PCR. Meanwhile, all their families were negative in all the specimen.
The induction of immune responses by the delivery of inactivated pathogens has been a standard and successful vaccination approach for many years, and licenced, inactivated vaccines for diseases such as poliomyelitis 63 and rabies 64 are commercially available. The long history of this approach is underpinned by a well‐defined regulatory framework that can be readily applied to new disease targets 65. The major challenge for the inactivated virus approach is that infection is not established, and therefore a full adaptive immune response is generally not achieved. However, because of the absence of living pathogens, these types of vaccines are safe and a basic capability to prepare such vaccines, especially for emergency use, might be worthwhile as a stop‐gap while alternative longer‐term approaches are developed. In this regard, studies of virus inactivation with X‐ray radiation (as a simple and cheap alternative to gamma irradiation by the use of radioactive isotopes), which maintain the tertiary antigenic structures of virus particles while destroying infectivity, have shown useful promise for a range of applications including vaccination (B. Afrough, unpublished).
Synthetic peptide‐based epitope‐vaccines (EVs) make use of short antigen‐derived peptide fragments that can be presented either to T cells or B cells 58. EVs offer several advantages over other forms of vaccines, particularly with regard to safety, ease of production, storage and distribution, without cold chain issues. They also offer the opportunity to vaccinate against several pathogens or multiple epitopes from the same pathogen. However, drawbacks include poor immunogenicity and the restriction of the approach to patients of a given tissue type [human leucocyte antigen (HLA) haplotype] 59 and, as such, they need to be tailored to accommodate the natural variation in HLA genes. Although initially this was thought to be a major impediment, new technologies have made this personalized‐medicine approach feasible 60, 61. Recently, bioinformatics tools have been developed to identify putative CD4+ T cell epitopes, mapped to the surface glycoproteins of the emerging viruses LASV, NipV and Hendra 62. While these vaccine candidates still need to be experimentally tested, the approach represents an interesting and novel strategy that shows promise for vaccination and which could also address immunity in particular target populations.
A multi-mAb microbicide has demonstrated 100% efficacy in a humanized mouse model. Broadly neutralizing HIV antibodies 2F5, 2G12, and 4E10 manufactured in mammalian cells and combined as MabGel have completed early clinical trials as a vaginal microbicide. A Nicotiana-manufactured (see Section 9 below) multi-mAb consisting of VRC01-N, 10E8-N, and HSV8-N as an HSV/HIV microbicide is currently in development (Mapp Biopharmaceutical, 2013). Nicotiana-manufactured 2G12 mAb that was vaginally delivered has completed a small clinical trial; no product-related adverse events were reported (Julian Ma, personal communication).
Since intracellular virus would be better protected than free virus from adverse effects of antiviral factors in the genital environment such as antiviral antibodies, and cell-cell transmission enables HIV-1 to evade inhibition by potent CD4bs directed antibodies, anti-cell mAbs [110, 111] will be an important component of a multi-mAb microbicide.
The emergence of multiresistant bacteria (Gram-positive cocci, Gram-negative rods, MDR tuberculosis, XDR tuberculosis, etc.) is a major global threat. During the past 4 years, many countries reported for the first time arrival of carbapenemases producing rods (32). Among others, New Delhi metallo-β-lactamase 1 has been isolated from Klebsiella pneumoniae and Escherichia coli worldwide, offering few treatment opportunities when these pathogens are involved in invasive diseases (33). Whereas this issue already constitutes a major concern in adult setting, data about epidemiology and optimal treatment options are even more limited in pediatrics. To avoid permanent extrapolation from adult data, we need well-conducted pediatric studies assessing the impact of various treatment strategies. As performed in adult setting (34), such kind of studies will help us to address crucial unanswered questions like what is the most suitable antibiotic options for a defined pathogen, which dosage use according to age groups, what is optimal duration of therapy, etc. Furthermore, the problem of resistance of fungal and viral infections should not be neglected and will increase in parallel with the broader use of immunosuppressive therapies and advances in bone marrow and solid organ transplants. New antiviral drugs against CMV or adenovirus infections have been recently developed and can be obtained in some instances on compassionate use, offering a last chance for some patients suffering from a disseminated uncontrolled viral disease (35). Again, data in children remain limited to some case series but these new drugs seem promising and their use is worth to be reported. In parallel, significant insights in specific immunotherapy to treat disseminated CMV, adenovirus, or EBV infections in transplanted patients offer an encouraging reliable approach to improve the prognosis of these serious illnesses (36).
To improve responsiveness to epidemics, in 2015 the WHO published a list of nine diseases requiring urgent vaccine R&D to prevent public health emergencies in the future. This list was revised in 2017, and key characteristics of the diseases prioritised by the WHO are summarised in Table 3. The process of prioritising diseases took into account properties of the causative pathogen e.g. transmissibility, host-based factors such as immunopathology, clinical aspects including ease of accurate diagnosis, availability of countermeasures and mortality, public health capacity and epidemiological factors.47 Research and development priorities for these diseases include development of suitable diagnostic tests, assessment of potential treatments, identification of key knowledge gaps, production platforms, behavioural interventions and acceleration of vaccine development. Preparation of sufficient quantities of safe and efficacious vaccines against potential outbreak pathogens is an extremely effective strategy. However, a lack of access to dedicated long-term funding has hampered vaccine development for outbreak pathogens in recent decades.48 As well as limiting the number of new vaccines being developed, the number of facilities with the capacity to biomanufacture vaccines is also limited, which is a significant issue for outbreak preparedness.49 In addition, WHO recognised that generally applicable platform technologies for rapid vaccine development are required and have set out to identify and prioritise the leading platforms.
To address these issues, the Coalition for Epidemic Preparedness Innovations (CEPI) was launched in January 2017, bringing together funders including the Wellcome Trust, the Bill and Melinda Gates Foundation, and the governments of Norway, Germany, Japan and others.50 The initial fund is $460 million, with the European Commission also pledging co-funding of €250 million and further funding due to be confirmed from the Government of India by the end of 2017. The fund will initially focus on the Nipah, Lassa and MERS viruses, aiming to bring two candidate vaccines through development against each disease. CEPI also aims to promote technical and institutional platforms to improve responsiveness to future epidemics. The approach undertaken by CEPI will advance vaccine development for diseases where research to date has been limited. This is in large part due to the lack of market potential for such vaccines in conjunction with the huge costs involved over a long period of time to provide a vaccine, from pre-clinical development through to licensure, estimated at upwards of $200 million to $500 million per vaccine.51 Therefore, the funding required to license a vaccine for each of the priority diseases highlighted by the WHO blueprint would run into many billions of dollars, and opportunities to assess the efficacy of these vaccines in humans would be rare.
Tumor initiation is usually a complex, multistep process involving environmental, biological, and genetic factors. Tumor viruses may play important roles in carcinogenesis; they might also contribute toward uncovering the cell growth pathways of cancer.
Although the clinical serological data suggest an association of EBV with NPC, the evidence from mechanistic studies and animal bioassays for the role of EBV infection in NPC occurrence is weaker than that for the role of EBV in lymphomas. Furthermore, the fact of universal EBV infection and the marked geographic and racial distributions of high-incidence NPC suggest that other co-factors may play more important roles in NPC initiation. Future studies to fulfill our proposed criteria are needed to clarify the role of EBV infection in NPC initiation, which would not only solve some of the mysteries of EBV biology, but also provide benefits in NPC prevention and treatment.
Lassa virus (LASV) is a medically relevant arenavirus which produces conditions ranging from asymptomatic infection to a lethal haemorrhagic fever, Lassa fever (LF). Annually, LASV appears to infect between 300,000 to 500,000 individuals with mortality rates ranging from 2% to in excess of 50% in outbreaks.66,67 LF is an endemic zoonosis in parts of West Africa including Nigeria, Liberia, Sierra Leone and Guinea, with more recent studies highlighting the spread of LASV into surrounding areas e.g. Mali, Benin and Ghana. This epidemiology suggests that efficacy trials of Lassa fever vaccines could be conducted successfully in countries such as Nigeria and Sierra Leone.
The common African rat (Mastomys natalensis) is the zoonotic reservoir for LASV and is thought to facilitate the ease of LASV spread to humans. Despite the recurrent and high disease incidence with associated significant morbidity and mortality, there are no approved vaccines. Currently, LF treatment relies on supportive care and, where available, the administration of the antiviral drug ribavirin.68 There continues to be an unmet need for medical interventions that can curb the spread of LASV and avert the morbidity and mortality associated with potential viral dissemination into a large geographical area due to the zoonotic reservoir.69,70
The first clinically available vaccine for the prevention of an arenavirus haemorrhagic fever was Candid #1, a live-attenuated vaccine against Junin virus infection, available through the Argentine National Immunization Plan.71 Unfortunately, the development of a LASV vaccine has not progressed as rapidly. Cellular immunity is thought to be critical for survival of LF infection, with early T cell activation associated with a better clinical outcome.72,73 Recent studies focusing on the early stages of LF in non-human primates (NHP) have confirmed previous observations that early and strong T-cell responses are associated with effective control of virus replication and recovery, while fatal LASV infection of NHP has been associated with a lack of peripheral T-cell activation.73,74 It has also been demonstrated that some vaccination strategies primarily aimed to elicit LASV-specific humoral immunity are not effective, e.g. gamma-irradiated LASV.75
The development of LASV vaccines has involved a number of different platform technologies including non-replicating vaccine approaches, such as inactivated LASV virus, virus-like particles (VLPs), and DNA vaccines, as well as replication-competent vaccine strategies (both recombinant and re-assortment viral vectored vaccines). The four replication-competent LASV vaccine candidates that have been extensively studied are based on vaccinia virus,76,77 vesicular stomatitis virus,78 Mopeia virus (MOPV)79 and yellow fever virus (YFV) 17D vectors80 with all of these vaccine candidates tested in different animal models, including NHPs.
Efficacy testing in animal models that mimic the major pathophysiological and immunological features of human LF are a prerequisite before licensure. Rodents are an obvious first species to establish immunogenicity, but as LASV has a rodent host reservoir and the response to LASV varies depending on mouse strain, age and inoculation route, rodents are not suitable as a valid LF disease model. Guinea pigs are the most sensitive model to study lung pathology,81,82 while common marmosets (CM) are surrogates to study liver involvement.83 However, LASV-infected rhesus and cynomolgus monkeys are considered the gold-standard models and are the only available and relevant challenge models for human LF.
The YFV vaccine strain 17D has been genetically manipulated to express the LASV glycoprotein and was designed to control both diseases, YF and LF, in areas of overlapping incidence in West Africa.84 While it can protect guinea pigs,80 it has failed to protect marmosets and is genetically unstable.86,87 In addition, while recombinant vesicular stomatitis virus (rVSV) expressing LASV glycoprotein was protective in nonhuman primate challenge, the protection was not sterile and LASV viremia could be measured post-infection.85
LASV and MOPV are closely related Old World arenaviruses that can exchange genomic segments (reassort) during coinfection. Clone ML29, encodes the major antigens of LASV and also MOPV antigens. Preclinically, both marmosets and guinea pigs have survived an otherwise fatal LASV infection.86,87 Recent studies have demonstrated that SIV-infected rhesus macaques respond well to ML29 vaccination, and survive when challenged with a heterologous lethal arenavirus strain (LCMV-WE) indicating that ML29 is both safe and immunogenic in immuno-compromised animals.88
Another vaccine vector that proved effective in guinea pigs against LASV challenge is a Venezuelan equine encephalitis virus (rVEE) replicon particle expressing GP or NP.89 Animals were fully protected against LASV challenge after prime/boost/boost immunization with this vector. One of the most promising vaccines is vaccinia virus encoding LASV glycoprotein; nonhuman primates vaccinated with this vaccine candidate were protected against challenge.90,91 However, despite several promising vaccine candidates in pre-clinical evaluation, none has yet advanced to a clinical trial in humans.
We emphasize the importance of using molecular diagnostic tests which can provide rapid diagnosis and lead to appropriate therapeutic strategies and epidemiological measures.
Though much is already known, it remains important to clarify the routes of human infection, including the role of the eyes in contracting infection, among primary human cases. The development of rapid molecular POCT tests and alternatives to serology, such as CD8+ detection can help us understand MERS-CoV transmission, which can lead to reductions in outbreaks. The scale of mild and subclinical cases among non-hospitalised Arabian Peninsula communities is unknown, as is their role in transmission. Most knowledge of MERS comes from studies of hospital-based populations or linked community contacts. Future prospective long-term cohort studies of mild community respiratory illnesses using molecular methods would be useful. Children have so far been largely absent from the MERS case tally, but they may represent an important population for prospective study. Recent lessons from the Zika and Ebola viruses should also inform new studies seeking possible long-term sequelae and viral persistence and highlight the need to follow-up severe MERS patients.
As mentioned in the above section, proper pediatric clinical trials with large sample sizes should be encouraged rather than always basing management of pediatric patients on extrapolation from adult studies. This is all the more important in the field of pharmacology of antimicrobials. Still too many drugs, including last available antimicrobials, are brought on the market without any pediatric-specific labeling or PK:PD data and lack reliable pediatric recommendations (26). It is common knowledge that drug metabolism differs among age groups, not only because of body surface but also because of variations in renal and hepatic drug excretion. Therefore, finding the optimal therapeutic dosage which offers a maximum safety and efficacy is challenging in children and particularly in neonates, even when following the results from blood drug monitoring (37). Huge differences exist when looking for example at metabolism and excretion of antifungals in newborns and infants compared to adults. Broader clinical trials are therefore warranted to determine the adequate dosages in each age group, especially in the youngest for which in addition major antifungals like voriconazole and posaconazole remain not indicated due to lack of safety data (38) restricting therapeutic options in case of invasive central nervous system fungal infection. Likewise, only few small pediatric studies assess the best dosage of new antibiotics like moxifloxacin or linezolid, and only few papers provide suitable data to guide our choice among the vast antibiotics armamentarium (39). More studies in children are needed that will compare the efficiency of different antibiotic schedules on morbidity, mortality, or in preventing recurrences of infections caused by common susceptible bacteria (e.g., MSSA) (40).
Three dromedary camels (CA1, CA2, CA3) and two alpaca (A1, A2) were vaccinated with an adjuvanted S1-protein subunit vaccine. Three camels (CA4, CA5, CA6) served as unvaccinated controls; CA6 is a historical control. Two alpaca (A3, A4) served as unvaccinated controls for the alpaca group. Animals were vaccinated on days 0 and 28 with 400 μg of S1 protein (Figure 1A) co-formulated with 40 mg AdvaxTM HCXL adjuvant (Vaxine Pty Ltd, Adelaide, Australia). The admixed product was delivered at each time point as two 1 mL intramuscular injections in each shoulder. All animals were boosted on day 105 with 400 μg of S1 protein emulsified in Sigma Adjuvant System (Sigma Aldrich Co. LLC. St. Louis, MO, USA) to complete a 0, 4-, and 15-week immunization schedule (Figure 1B). Serum from vaccinated animals was collected and evaluated by plaque reduction neutralization test (PRNT) with MERS-CoV strain HCoV-EMC/2012 (Figure 1C). On day 28 after priming vaccination, low levels of MERS-CoV neutralizing antibodies were detected in two of three the camels (virus neutralizing titers of 1:40, 1:10, and <10 respectively; Figure 1C). The day 28 boost did not result in an increase in neutralizing titers in the PRNT assay and neutralizing titers decreased between the second and third boost. The third immunization resulted in a quick increase in neutralizing titer in the two camels that responded to the vaccine; neutralizing titers were high in these two camels by the time of challenge. Neutralizing antibodies were not detected in CA3 (<1:10) at any point during the experiment (Figure 1C). A stronger neutralizing response was observed in the alpaca after vaccination, with virus neutralizing titers of 1:640 and 1:40 four weeks after the initial vaccination to end titers of 1:2560 and 1:640 at the time of challenge (Figure 1C).
The central nervous system (CNS), a marvel of intricate cellular and molecular interactions, maintains life and orchestrates homeostasis. Unfortunately, the CNS is not immune to alterations that lead to neurological disease, some resulting from acute, persistent or latent viral infections. Several viruses have the ability to invade the CNS, where they can infect resident cells, including the neurons. Although rare, viral infections of the CNS do occur. However, their incidence in clinical practice is difficult to evaluate precisely. For instance, in cases of viral encephalitis involving the most prevalent viruses known to reach the CNS (mainly herpesviruses, arboviruses and enteroviruses), an actual viral presence can only be detected in 3 to 30 cases out of 100,000 persons. Considering all types of viral infections, between 6000 and 20,000 cases of encephalitis that require hospitalization occur every year in the United States, representing about 6 cases per 100,000 infected persons every year. As the estimated charge for each case lies between $58,000 and $89,600, an evaluation of the total annual health cost is of half a billion dollars. Due to the cost associated with patient care and treatment, CNS viral infections cause considerably more morbidity and disabilities in low-income/resource-poor countries.
Very common worldwide, viral infections of the respiratory tract represent a major problem for human and animal health, imposing a tremendous economic burden. These respiratory infections induce the most common illnesses and are a leading cause of morbidity and mortality in humans worldwide, causing critical problems in public health, especially in children, the elderly and immune-compromised individuals. Viruses represent the most prevalent pathogens present in the respiratory tract. Indeed, it is estimated that about 200 different viruses (including influenza viruses, coronaviruses, rhinoviruses, adenoviruses, metapneumoviruses, such as human metapneumovirus A1, as well as orthopneumoviruses, such as the human respiratory syncytial virus) can infect the human airway. Infants and children, as well as the elderly represent more vulnerable populations, in which viruses cause 95% and 40% of all respiratory diseases, respectively. Among the various respiratory viruses, some are constantly circulating every year in the human populations worldwide, where they can be associated with a plethora of symptoms, from common colds to more severe problems requiring hospitalization. Moreover, in addition to the many “regular” viruses that circulate and infect millions of people every year, new respiratory viral agents emerge from time to time, causing viral epidemics or pandemics associated with more serious symptoms, such as neurologic disorders. These peculiar events usually take place when RNA viruses like influenza A, human coronaviruses, such as MERS-CoV and SARS-CoV, or henipaviruses, present in an animal reservoir, cross the species barrier as an opportunistic strategy to adapt to new environments and/or new hosts. These zoonoses may have disastrous consequences in humans, and the burden is even higher if they have neurological consequences.