ArticleLiterature Review

Feasibility of Aerosol Vaccination in Humans

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Abstract

The feasibility of using aerosol vaccines to achieve mass and rapid immunization, especially in developing countries and disaster areas, is being assessed on the basis of current available information. The aerosol mode of vaccine introduction, which best follows the natural route of many infections, may first lead to development of immunity at the portal of entry, and may also induce a more generalized defense. The recommended optimal way of introducing an aerosol vaccine is nasal breathing, which is more suitable for geriatric and pediatric populations, permits use of greater antigen volumes, and allows easier monitoring of results. Technical requirements for ideal aerosol vaccines and delivery systems, possible adverse effects, and cost-effectiveness are other issues addressed. Several thousand human subjects have been aerosol-vaccinated over a period of many years in Russia with live-attenuated strains against many diseases. Extensive field trials in South America with aerosolized live-attenuated measles vaccine have also been successful, and excellent results have been reported with pilot projects employing inactivated or live-attenuated aerosol influenza A vaccine. We conclude that aerosol immunization seems a promising method of vaccination. Although some basic information is still lacking, this method has already been used successfully in large populations and has therefore passed the phase of initial feasibility evaluation.

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... Studies have also shown that mucosal immunity induced via intranasal delivery provides cross-protection against heterologous strains9101112131415, and enhances heterosubtypic immunity for protection against multiple influenza A subtypes [9,10,16,17]. Other logistical advantages of an intranasal vaccine include the reduced risk of infection and contamination due to the non-use of needles and syringes, and avoiding the need for disposal strategies of sharps after mass vaccination campaigns181920. The currently licensed intranasal vaccine FluMist™ is a live-attenuated virus administered using a Becton- Dickenson AccuSpray™ device which generates a highspeed spray of large vaccine particles, with a mass median aerosol diameter (MMAD) > 70 μm. ...
... In contrast, controlled aerosolization helps to minimize vaccine particle size variability and ensures delivery to the lower respiratory tract and internal target airways [21]. In animals, aerosol vaccination is currently used globally to immunize poultry against Newcastle disease and shows promise of successful immunization in fowls and pigs against a variety of diseases including fowlpox, infectious bronchitis, hog cholera, pseudorabies, erysipelas, gastroenteritis, pasteurellosis , and mycoplasmosis [19]. Notably, aerosol measles vaccination of 4 million Mexican schoolchildren in 1989-90 demonstrated a seroconversion rate of 52- 64% (similar to subcutaneous administration) and an overall efficacy of 96%, with excellent public acceptance and fewer side effects than subcutaneous vaccination [22] . ...
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Conventional parenteral injection of vaccines is limited in its ability to induce locally-produced immune responses in the respiratory tract, and has logistical disadvantages in widespread vaccine administration. Recent studies suggest that intranasal delivery or vaccination in the respiratory tract with recombinant viral vectors can enhance immunogenicity and protection against respiratory diseases such as influenza and tuberculosis, and can offer more broad-based generalized protection by eliciting durable mucosal immune responses. Controlled aerosolization is a method to minimize vaccine particle size and ensure delivery to the lower respiratory tract. Here, we characterize the dynamics of aerosolization and show the effects of vaccine concentration on particle size, vector viability, and the actual delivered dose of an aerosolized adenoviral vector. In addition, we demonstrate that aerosol delivery of a recombinant adenoviral vaccine encoding H1N1 hemagglutinin is immunogenic and protects ferrets against homologous viral challenge. Overall, aerosol delivery offers comparable protection to intramuscular injection, and represents an attractive vaccine delivery method for broad-based immunization campaigns.
... To create mass and rapid immunization, a nasally applicated aerosol vaccine has a great potential. Development of nasal immunity and generalized immunization in a whole population has been proven succesfully in several pilot studies in Russia and South America 153 . Roth et al. gives a good overview of the potential of aerosol immunization as it seems promising in cost -effectiveness, side effects and technical requirements 153 . ...
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It has been suggested that intranasal (IN) drug delivery could be used to administer drugs directly to the brain, bypassing the blood-brain barrier. Conclusive evidence of this proposed route of drug transport has not been observed by IN-IV comparison. In eight neurosurgery patients with a CSF drain, the uptake in CSF and plasma after IN and IV drug administration was compared. No evidence of direct access of the drugs from the nose to the CSF was found.
... Many biological products are at their clinical stage of development for the delivery of therapeutic peptides with indications for cystic ibrosis, in luenza virus, in lammation sarcoma, tuberculosis, and diabetes as summarized by Andrade et al., 2014 [174] in tables 7.1 and 7.2. The immunization through this route may provide excellent irst barrier in the prevention of some disease, especially in the developing countries [175,176]; however, delivery of vaccines through the pulmonary route is still under the early stages of development. In spite of the success in delivery of some biopharmaceuticals, more developmental stages are required to enhance its ef icacy in a safe and easy way to guarantee the optimum activity of the drug in its target tissues. ...
... Transmission of influenza virus via aerosols has been proven experimentally in mice (Schulman and Kilbourne 1963). In humans, the effectiveness of aerosol transmission is further supported in vaccination experiments with live-attenuated vaccines via aerosols versus other routes (Roth et al. 2003). ...
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A qualitative risk assessment was conducted to determine 1) the likelihood of introduction of Asian lineage H5N1 highly pathogenic avian influenza virus by migratory birds into the EU, 2) the likelihood of it becoming endemic in wild birds in the EU and 3) the likelihood of transmission of infection to domestic poultry. The conclusions reached included that the probability of the virus being released into the EU varied between low and high, depending on the species of migratory birds. A minority opinion was noted concluding that the risk was medium across species. In the light of this risk, it was recommended to educate poultry keepers in currently affected countries outside the EU in relation to minimum biosecurity standards. Surveillance should be enhanced in these countries in domestic poultry and wild birds, and vaccination programmes should be considered for controlling the infection. Trade with poultry and their products needs to be managed considering the risks of spreading virus between geographical areas. Research needs to be conducted to improve surveillance methods in poultry and widl birds. Wild bird migration data needs to be analysed to better understand the flyways used by the various species. The risk of the virus becoming endemic in European wild bird populations was considered to vary between low and high depending on species. A minority opinion was received concluding that this risk was medium across species. This risk could be reduced by intensifying surveillance in wild birds within the EU, and use the data to inform biosecurity measures in domestic birds. The behaviour of wild birds within the EU needs to be better studied so that the dynamics of transmission within and between species are better understood. The final step of the risk assessment indicates that there is a negligible risk of the virus infecting domestic poultry kept under a high biosecurity standard and not in high poultry density areas. The risk increases to very low if they are kept in high poultry density areas. For backyard and free-range poultry, and any poultry not kept under high biosecurity standards, it was concluded that the risk of introduction of Asian lineage H5N1 highly pathogenic avian influenza virus to the flock was low to medium. These risks emphasize the need to make better use of existing and new migratory bird behaviour data. Passive and active surveillance for AI in wild birds needs to be intensified. It should focus on the species identified in this risk assessment. Biosecurity measures for poultry holdings need to be reviewed, and research needs to be conducted to optimise their effectiveness. Poultry holdings should not be built in the vicinity of wetland areas. New vaccines and their use need to be researched.
... Presentation of a suitable antigen with an appropriate adjuvant to the nasal-associated lymphoid tissue (NALT) has the potential to induce humoral and cellular immune responses (Zuercher et al., 2002). This approach may be a particularly effective approach to achieving rapid mass immunization, for instance in children and/or in developing countries and disaster areas (Roth et al., 2003). IN immunization may lead to development of local, as well as systemic, immunity. ...
Article
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Intranasal drug delivery – which has been practiced for thousands of years, has been given a new lease of life. It is a useful delivery method for drugs that are active in low doses and show no minimal oral bioavailability such as proteins and peptides. One of the reasons for the low degree of absorption of peptides and proteins via the nasal route is rapid movement away from the absorption site in the nasal cavity due to the Mucociliary Clearance mechanism. The nasal route circumvents hepatic first pass elimination associated with the oral delivery: it is easily accessible and suitable for self-medication. The large surface area of the nasal mucosa affords a rapid onset of therapeutic effect, potential for direct-to-central nervous system delivery, no first-pass metabolism, and non-invasiveness; all of which may maximize patient convenience, comfort, and compliance. IN delivery is non-invasive, essentially painless, does not require sterile preparation, and is easily and readily administered by the patient or a physician, e.g., in an emergency setting. Furthermore, the nasal route may offer improved delivery for “non-Lipinski” drugs.
... The aerosolized vaccine best follows the natural route of many infections. 18 The IgG binding antibodies were robustly increased at 1-month post-prime vaccination ( Supplementary Fig. 2b), and the 50% inhibitory concentration (IC 50 ) were boosted by 5.8-, 4.9-, and 3.8-fold on average for the Wuhan-Hu-1, Beta, and Delta variants, respectively, from the prime dose to the second vaccine dose ( Supplementary Fig. 2c). Blood samples from donor 3, with the highest neutralization titers of plasma IgG, were chosen for longitudinal analysis to monitor the induction and maintenance of antibody responses to vaccination against SARS-CoV-2 variants. ...
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The SARS-CoV-2 Omicron variant shows substantial resistance to neutralization by infection- and vaccination-induced antibodies, highlighting the demands for research on the continuing discovery of broadly neutralizing antibodies (bnAbs). Here, we developed a panel of bnAbs against Omicron and other variants of concern (VOCs) elicited by vaccination of adenovirus-vectored COVID-19 vaccine (Ad5-nCoV). We also investigated the human longitudinal antibody responses following vaccination and demonstrated how the bnAbs evolved over time. A monoclonal antibody (mAb), named ZWD12, exhibited potent and broad neutralization against SARS-CoV-2 variants Alpha, Beta, Gamma, Kappa, Delta, and Omicron by blocking the spike protein binding to the angiotensin-converting enzyme 2 (ACE2) and provided complete protection in the challenged prophylactic and therapeutic K18-hACE2 transgenic mouse model. We defined the ZWD12 epitope by determining its structure in complex with the spike (S) protein via cryo-electron microscopy. This study affords the potential to develop broadly therapeutic mAb drugs and suggests that the RBD epitope bound by ZWD12 is a rational target for the design of a broad spectrum of vaccines.
... Vaccination by inhalation was pioneered in the 1980s by Albert Sabin and his colleagues who were vaccinating children in Mexico against measles using an aerosolised vaccine [37]. By the mid-1990s, it was clear that this is an effective means of measles vaccination and accordingly several investigators began to consider the possibility of mass vaccination campaigns with an aerosolised measles vaccine in other developing countries [38,39]. ...
Article
The lung is composed of two major anatomically distinct regions: the conducting airways (tracheo-bronchial region) and the gas-exchanging airspaces (alveolar region). The conducting airways can be further subdivided into the trachea plus larger bronchi and the distal bronchiolar airways. Each of these regions consists of distinct types of epithelial cells with unique phenotypes, morphologies and associated physiological functions. This chapter focuses on various model systems that have been utilised to study drug transport and metabolism in the adult tracheo-bronchial epithelium. This includes primary cell cultures, airway cell lines and culture systems with or without the cystic fibrosis gene deletion. The permeability of increasing numbers of compounds in these drug absorption models has been reported. Cell culture systems are particularly amenable to the study of transport mechanisms and the expression of a variety of active transport mechanisms in airway cell culture systems is summarised. Another application of epithelial cell models is to predict drug absorption in vivo. The drug metabolising capacity of electrically tight and non-barrier forming airway cell models is also summarised in terms of the P450, phase II enzymes plus peptidase and protease activity.
... 3,4 Insulin, human growth hormone, vaccines for influenza and measles and gene therapies for cystic fibrosis have been clinically administered to patients via the lungs. [5][6][7][8][9] Until recently, the formulations developed for pulmonary delivery have been limited to the active substances and a restricted list of excipients essentially devoted to allow and regulate the aerosolization process. As a consequence, the in vivo fate of the drug, i.e. interaction with lung epithelia, residence time, dissolution and therapeutic efficacy, was essentially determined by the physicochemical properties of the active substance. ...
... (2,3) In recent years, aerosol inhalation has also been considered as an alternative route of vaccine delivery. (4)(5)(6) Vaccination is mostly performed in children, and this presents particular challenges for efficient pulmonary delivery and dose control. (7,8) This is especially true in very young infants who have low tidal volumes (9) and variable breathing patterns. ...
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Background: In pre-clinical animal studies, the uniformity of dosing across subjects and routes of administration is a crucial requirement. In preparation for a study in which aerosolized live-attenuated measles virus vaccine was administered to cynomolgus monkeys (Macaca fascicularis) by inhalation, we assessed the percentage of a nebulized dose inhaled under varying conditions. Methods: Drug delivery varies with breathing parameters. Therefore we determined macaque breathing patterns (tidal volume, breathing frequency, and inspiratory to expiratory (I:E) ratio) across a range of 3.3-6.5 kg body weight, using a pediatric pneumotachometer interfaced either with an endotracheal tube or a facemask. Subsequently, these breathing patterns were reproduced using a breathing simulator attached to a filter to collect the inhaled dose. Albuterol was nebulized using a vibrating mesh nebulizer and the percentage inhaled dose was determined by extraction of drug from the filter and subsequent quantification. Results: Tidal volumes ranged from 24 to 46 mL, breathing frequencies from 19 to 31 breaths per minute and I:E ratios from 0.7 to 1.6. A small pediatric resuscitation mask was identified as the best fitting interface between animal and pneumotachometer. The average efficiency of inhaled dose delivery was 32.1% (standard deviation 7.5, range 24%-48%), with variation in tidal volumes as the most important determinant. Conclusions: Studies in non-human primates aimed at comparing aerosol delivery with other routes of administration should take both the inter-subject variation and relatively low efficiency of delivery to these low body weight mammals into account.
... In particular, HBcAg acts as a Th1 adjuvant and has a synergistic effect on antibody production and cellular responses when co-administered with HBsAg. 55,58,59 In the Phase I clinical trial, 19 healthy male adults were enrolled to evaluated the safety profile and immunogenicity of NASVAC for nasal administration. The participants received either NASVAC (50 mg HBsAg and 50 mg HBcAg) or placebo (0.9% physiologic saline) on day 0, 7, 15, 30, and 60, respectively. ...
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Hepatitis B virus (HBV) is a member of Hepadnavirus family, which leads to chronic infection in around 5% of patients with a high risk of developing liver cirrhosis, liver failure, and hepatocellular carcinoma.¹ Wright TL, Lau JY. Clinical aspects of hepatitis B virus infection. Lancet 1993; 342:1340-4.[CrossRef], [PubMed], [Web of Science ®] Despite the availability of prophylactic vaccines against hepatitis B for over three decades, there are still more than two billion people have been infected and 240 million of them were chronic. Antiviral therapies currently used in the treatment of CHB (chronic hepatitis B) infection include peg-interferon, standard α-interferon and nucleos/tide analogues (NAs), but none of them can provide sustained control of viral replication. As an alternative strategy, therapeutic vaccines for CHB patients have been widely studied and showed some promising efficacies in dozens of preclinical and clinical trials. In this article, we review current research progress in several types of therapeutic vaccines for CHB treatment, including protein-based vaccines, DNA-based vaccines, live vector-based vaccines, peptide-based vaccines and cell-based therapies. These researches may provide some clues for developing new treatments in CHB infection.
... Carrier helps to improve the active pharmaceutical ingredient properties to inhale. Various systemic drugs, recombinant human granulocyte colony stimulating factor, insulin, drugs to treat bone disorders, and vaccines are used as inhaled medication to treat diseases [6] . 90 % w/w of carrier is widely used in dry powder inhaler formulation. ...
Article
The therapy was carried out by inhalation of medicinal plants to cure illness of respiratory tract by anicient peoples. In the modern days extraction of medicinal plants filled in soft gelatin capsule dispersed in hot water and was inhaled to cure allergic cough, asthma and other respiratory diseases, are manage to cure the patient with the inhalation of respiratory drugs. The inhalers are metered dose inhalers, dry powder inhaler, nebulizer and inhalable solution. © 2017, Indian Pharmaceutical Association. All rights reserved.
... 22 Multiple factors affect airborne survival of microbes indoors (Table 1). 13,31 The effect of these factors on different types of microbes varies, and generalizations can be difficult because of differences in the experimental methodologies used. 27 Air temperature, relative humidity (RH), and turbulence are among the more important factors affecting the fate and spread of infectious agents indoors. ...
Article
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Indoor air can be an important vehicle for a variety of human pathogens. This review provides examples of airborne transmission of infectious agents from experimental and field studies and discusses how airborne pathogens can contaminate other parts of the environment to give rise to secondary vehicles leading air-surface-air nexus with possible transmission to susceptible hosts. The following groups of human pathogens are covered because of their known or potential airborne spread: vegetative bacteria (staphylococci and legionellae), fungi (Aspergillus, Penicillium, and Cladosporium spp and Stachybotrys chartarum), enteric viruses (noro- and rotaviruses), respiratory viruses (influenza and coronaviruses), mycobacteria (tuberculous and nontuberculous), and bacterial spore formers (Clostridium difficile and Bacillus anthracis). An overview of methods for experimentally generating and recovering airborne human pathogens is included, along with a discussion of factors that influence microbial survival in indoor air. Available guidelines from the U.S. Environmental Protection Agency and other global regulatory bodies for the study of airborne pathogens are critically reviewed with particular reference to microbial surrogates that are recommended. Recent developments in experimental facilities to contaminate indoor air with microbial aerosols are presented, along with emerging technologies to decontaminate indoor air under field-relevant conditions. Furthermore, the role that air decontamination may play in reducing the contamination of environmental surfaces and its combined impact on interrupting the risk of pathogen spread in both domestic and institutional settings is discussed.
... We believe that our chosen delivery strategy also had an important bearing on our findings. In addition to the aforementioned dose, targeting and side-effect issues, administering radioprotection via aerosol offers many of the same advantages that are cited in the context of mass vaccination by the same route -namely ease and speed of application by nonmedical personnel, non-invasiveness which results in greater social acceptance, reduced risk of cross-contamination of blood-born infectious agents, diminished medical waste, and potentially lower costs 78,79 . Further studies will examine the ability of aerosolized surfactant to alter pathological, molecular and gene expression changes following altered dosing and fractionation schemes with prolonged assessment periods. ...
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Methods to protect against radiation-induced lung injury (RILI) will facilitate the development of more effective radio-therapeutic protocols for lung cancer and may provide the means to protect the wider population in the event of a deliberate or accidental nuclear or radiological event. We hypothesised that supplementing lipid membranes through nebulization of synthetic lamellar lipids would mitigate RILI. Following pre-treatment with either nebulised lamellar lipids or saline, anaesthetised sheep were prescribed fractionated radiotherapy (30 Gray (Gy) total dose in five 6 Gy fractions at 3-4 days intervals) to a defined unilateral lung volume. Gross pathology in radio-exposed lung 37 days after the first radiation treatment was consistent between treatment groups and consisted of deep red congestion evident on the pleural surface and firmness on palpation. Consistent histopathological features in radio-exposed lung were subpleural, periarteriolar and peribronchial intra-alveolar oedema, alveolar fibrosis, interstitial pneumonia and type II pneumocyte hyperplasia. The synthetic lamellar lipids abrogated radiation-induced alveolar fibrosis and reduced alpha-smooth muscle actin (ASMA) expression in radio-exposed lung compared to saline treated sheep. Administration of synthetic lamellar lipids was also associated with an increased number of cells expressing dendritic cell-lysosomal associated membrane protein throughout the lung.
... Appropriate antigen with a good adjuvant to the nasal-associated with lymphoid tissue has the ability to encourage humoral and cellular immune responses [10] . This approach may be particularly effective for achieving rapid mass immunization, for instance in children and/or in developing countries and disaster areas [11] . The intranasal immunization can lead to the development of both local and systemic immunity. ...
... Nasal vaccines have been formulated in various forms, such as aerosols [38], liposomes [39] and microspheres [40] and delivered through the nostrils together with or without adjuvants [41,42]. The use of adjuvants such as adamantylamide dipeptide [43] and macrophage-activating lipopeptide [44,45] is sometimes obligatory to attain adequately high immune responses with inactivated vaccines. ...
Article
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Despite successful use, needle-based immunizations have several issues such as the risk of injuries and infections from the reuse of needles and syringes and the low patient compliance due to pain and fear of needles during immunization. In contrast, needle-free immunizations have several advantages including ease of administration, high level of patient compliance and the possibility of mass vaccination. Thus, there is an increasing interest on developing effective needle-free immunizations via cutaneous and mucosal approaches. Here, we discuss several methods of needle-free immunizations and provide insights into promising use of chitosan systems for successful immunization.
... In the last century, major trials were performed in the former Soviet Union where several thousand humans were successfully aerosol vaccinated over a period of many years with liveattenuated strains such as dry anthrax spores [16,47]. The first major clinical trial was probably performed by Albert Sabin and colleagues in Mexico in the 1980s when around 4 million children were vaccinated by a nebulised attenuated Edmonston Zagreb measles vaccine. ...
Article
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Vaccine delivery via mucosal surfaces is an interesting alternative to parenteral vaccine administration, as it avoids the use of a needle and syringe. Mucosal vaccine administration also targets the mucosal immune system, which is the largest lymphoid tissue in the human body. The mucosal immune response involves systemic, antigen-specific humoral and cellular immune response in addition to a local response which is characterised by a predominantly cytotoxic T cell response in combination with secreted IgA. This antibody facilitates pathogen recognition and deletion prior to entrance into the body. Hence, administration via the respiratory mucosa can be favoured for all pathogens which use the respiratory tract as entry to the body, such as influenza and for all diseases directly affecting the respiratory tract such as pneumonia. Additionally, the different mucosal tissues of the human body are interconnected via the so-called “common mucosal immune system”, which allows induction of an antigen-specific immune response in distant mucosal sites. Finally, mucosal administration is also interesting in the area of therapeutic vaccination, in which a predominant cellular immune response is required, as this can efficiently be induced by this route of delivery. The review gives an introduction to respiratory vaccination, formulation approaches and application strategies.
... Indeed, aerosol-based treatments have recently become more widely used to accomplish a variety of tasks. Inhalation therapies have expanded from bronchodilators or antibiotics to more advanced treatments such as systemic gene therapies, needle free vaccinations, and insulin therapy for diabetic patients [10][11][12]. This surge in applications of inhalation therapies is driven by several factors. ...
Article
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As the range of applications of organs-on-chips is broadening, the evaluation of aerosol-based therapies using a lung-on-a-chip model has become an attractive approach. Inhalation therapies are not only minimally invasive but also provide optimal pharmacokinetic conditions for drug absorption. As drug development evolves, it is likely that better screening through use of organs-on-chips can significantly save time and cost. In this work, bio-aerosols of various compounds including insulin were generated using a jet nebulizer. The aerosol flows were driven through microfluidic bilayer devices establishing an air–liquid interface to mimic the blood–air barrier in human small airways. The aerosol flow in the microfluidic devices has been characterized and adjusted to closely match physiological values. The permeability of several compounds, including paracellular and transcellular biomarkers, across epithelial/endothelial cell barriers was measured. Concentration–time plots were established in microfluidic devices with and without cells; the curves were then utilized to extract standard pharmacokinetic parameters such as the area under the curve, maximum concentration, and time to maximum concentration. The cell barrier significantly affected the measured pharmacokinetic parameters, as compound absorption through the barrier decreases with its increasing molecular size. Aerosolizing insulin can lead to the formation of fibrils, prior to its entry to the microfluidic device, with a substantially larger apparent molecular size effectively blocking its paracellular transport. The results demonstrate the advantage of using lung-on-a-chip for drug discovery with applications such as development of novel inhaled therapies.
... At this juncture, we propose a SARS-CoV-2 aerosolbased vaccine based on a lasso-like phosphorothioate oligonucleotide construction containing CpG motifs and antigen-presenting unique sequence (APUS) (Fig. 1). Aerosol immunization seems to be a promising method of vaccination [87,88], including as it does aerosolized delivery of nucleic acids optimized for lung uptake [89] and nasal spray [90]. Several independent studies have now demonstrated that the dependence on CpG motifs for TLR9 activation is Fig. 1 Structure of a SARS-CoV-2 vaccine based on a lasso-like phosphorothioate oligonucleotide construction containing CpG motifs and antigen-presenting unique ACG-containing genome sequence of SARS-CoV-2 (performed by RNAfold WebServer; https ://rna.tbi.univi ...
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During the current COVID-19 pandemic, the global ratio between the dead and the survivors is approximately 1 to 10, which has put humanity on high alert and provided strong motivation for the intensive search for vaccines and drugs. It is already clear that if we follow the most likely scenario, which is similar to that used to create seasonal influenza vaccines, then we will need to develop improved vaccine formulas every year to control the spread of the new, highly mutable coronavirus SARS-CoV-2. In this article, using well-known RNA viruses (HIV, influenza viruses, HCV) as examples, we consider the main successes and failures in creating primarily highly effective vaccines. The experience accumulated dealing with the biology of zoonotic RNA viruses suggests that the fight against COVID-19 will be difficult and lengthy. The most effective vaccines against SARS-CoV-2 will be those able to form highly effective memory cells for both humoral (memory B cells) and cellular (cross-reactive antiviral memory T cells) immunity. Unfortunately, RNA viruses constantly sweep their tracks and perhaps one of the most promising solutions in the fight against the COVID-19 pandemic is the creation of 'universal' vaccines based on conservative SARS-CoV-2 genome sequences (antigen-presenting) and unmethylated CpG dinucleotides (adjuvant) in the composition of the phosphorothioate backbone of single-stranded DNA oligonucleotides (ODN), which can be effective for long periods of use. Here we propose a SARS-CoV-2 vaccine based on a lasso-like phosphorothioate oligonucleotide construction containing CpG motifs and the antigen-presenting unique ACG-containing genome sequence of SARS-CoV-2. We found that CpG dinucleotides are the most rare dinucleotides in the genomes of SARS-CoV-2 and other known human coronaviruses, and hypothesized that their higher frequency could be responsible for the unwanted increased lethality to the host, causing a 'cytokine storm' in people who overexpress cytokines through the activation of specific Toll-like receptors in a manner similar to TLR9-CpG ODN interactions. Interestingly, the virus strains sequenced in China (Wuhan) in February 2020 contained on average 1 CpG dinucleotide more in their genome than the later strains from the USA (New York) sequenced in May 2020. Obviously, during the first steps of the microevolution of SARS-CoV-2 in the human population, natural selection tends to select viral genomes containing fewer CpG motifs that do not trigger a strong innate immune response, so the infected person has moderate symptoms and spreads SARS-CoV-2 more readily. However, in our opinion, unmethylated CpG dinucleotides are also capable of preparing the host immune system for the coronavirus infection and should be present in SARS-CoV-2 vaccines as strong adjuvants.
... Vaccine delivery by aerosol has potential advantages, including the induction of local immune responses at the site of infection and the practical advantage of needle-free delivery [9][10][11][12][13]. ...
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The immunogenicity of the candidate tuberculosis (TB) vaccine MVA85A may be enhanced by aerosol delivery. Intradermal administration was shown to be safe in adults with latent TB infection (LTBI), but data are lacking for aerosol-delivered candidate TB vaccines in this population. We carried out a Phase I trial to evaluate the safety and immunogenicity of MVA85A delivered by aerosol in UK adults with LTBI (NCT02532036). Two volunteers were recruited, and the vaccine was well-tolerated with no safety concerns. Aerosolised vaccination with MVA85A induced mycobacterium- and vector-specific IFN-γ in blood and mycobacterium-specific Th1 cytokines in bronchoalveolar lavage. We identified several important barriers that could hamper recruitment into clinical trials in this patient population. The trial did not show any safety concerns in the aerosol delivery of a candidate viral-vectored TB vaccine to two UK adults with Mycobacterium tuberculosis (M.tb) infection. It also systemically and mucosally demonstrated inducible immune responses following aerosol vaccination. A further trial in a country with higher incidence of LTBI would confirm these findings.
... The feasibility of using the lung as a portal for delivery of vaccines has been reviewed previously (Roth et al., 2003;Laube, 2005). These two papers outline previous trials of aerosol vaccination on humans against anthrax, tetanus and botulinum toxoids, measles and plague. ...
Thesis
DNA vaccines have emerged to be an alternative to conventional vaccines due to their increased safety compared with recombinant protein vaccines and live/attenuated vaccines. Pulmonary delivery of vaccines could offer additional advantages, because from an immunological point of view, there is a large presence of macrophages for antigen/DNA uptake and it also part of the mucosal immune system, which is important for effective immune protection. Encapsulating the DNA into a particulate delivery system would be advantageous for protection against degrading nucleases. The aim of this project was to produce microparticles encapsulating plasmid DNA with a high loading efficiency, appropriate size suitable for pulmonary delivery and with the maintenance of plasmid DNA conformation. Microparticles were produced using poly(DL-lactide-co-glycolide) as the polymer due to its well-known biodegradable and biocompatibility characteristics, and polyvinyl alcohol (PVA) as the main stabiliser. Plasmid DNA encoding for luciferase protein was used as a model plasmid for studies. Water-in-oil-in-water (w1/o/w2) was used as the method for making particles. Factorial experimental design was used to rapidly optimize a formulation that had the desired properties. Further studies examined the effect of adding various excipients (0.1M NaHCO3, 1% m/m Na2HPO 4) on the loading, diameters, morphology and charge on the microparticles. Analytical (including TGA, NMR and DSC) and cell culture experiments - using a human alveolar cell line (A549) and mouse macrophage/monocyte cell line (J774A.1) - were carried out to analyse their physical and biological properties. The factorial experimental design aided in choosing a platform formulation, with particle diameters of 2-5 μm and loading of 66-72% m/m. Particles without added excipients had low plasmid DNA loading and the DNA had lost most of its original conformation. However, addition of buffers into the aqueous phases, particularly 1% m/v NaH2PO4, reduced the loss of conformation and enhanced loading efficiency. Physicochemical studies gave mixed results on the formulations tested in terms of thermal stability, DCM and PVA levels and performance as a dry powder. Results demonstrated that microparticles made without buffer were more thermally stable, had lower residual DCM and PVA levels in contrast to those made with 1% m/v Na2HPO4 and 0.1M NaHCO3 . The microparticles did not aerosolise well as a dry powder - even with addition of surfactants such as lecithin and DPPC - with diameters between 69-95 μm being measured, which is in contrast to the diameters measured in a 'wet' state (2-5 μm). Cell culture studies demonstrated that entrapped DNA (which was extracted out from the particles and delivered to cells using a commercial agent) was still biologically active, but the A549 cell line was much easier to transfect than the J774A.1 cells. However, the microparticles themselves were poor delivery vehicles of DNA in these models. Overall, these experiments demonstrated the range of factors that need to be considered when trying to create suitable microparticulate carriers for pulmonary delivery of DNA vaccines.
... The survival of airborne microorganisms indoors is significantly influenced by several environmental factors. These factors include temperature, relative humidity (RH), atmospheric gases, ultraviolet irradiation and surrounding organic material [10,11]. Air temperature and RH are the factors that most affect the persistence and spread of airborne microorganisms indoors [12]. ...
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Air is recognized as an important source of microbial contamination in food production facilities and has the potential to contaminate the food product causing food safety and spoilage issues for the food industry. Potential for aerial microbial contamination of food can be a particular issue during storage in cold rooms when the food is not packaged and is exposed to contaminated air over a prolonged period. Thus, there are potential benefits for the food industry for an aerial decontamination in cold storage facilities. In this paper, aerial decontamination approaches are reviewed and challenges encountered for their applications are discussed. It is considered that current systems may not be completely effective and environmentally friendly, therefore, it is of great significance to consider the development of nonresidual and verified decontamination technologies for the food industry and, in particular, for the cold storage rooms.
... The survival of airborne microorganisms indoors is significantly influenced by several environmental factors. These factors include temperature, relative humidity (RH), atmospheric gases, ultraviolet irradiation and surrounding organic material [10,11]. Air temperature and RH are the factors that most affect the persistence and spread of airborne microorganisms indoors [12]. ...
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The neuraminidase protein of influenza viruses is a surface glycoprotein that shows enzymatic activity to remove sialic acid, the viral receptor, from both viral and host proteins. The removal of sialic acid from viral proteins plays a key role in the release of the virus from the cell by preventing the aggregation of the virus by the hemagglutinin protein binding to other viral proteins. Antibodies to the neuraminidase protein can be protective alone in animal challenge studies, but the neuraminidase antibodies appear to provide protection in a different manner than antibodies to the hemagglutinin protein. Neutralizing antibodies to the hemagglutinin protein can directly block virus entry, but protective antibodies to the neuraminidase protein are thought to primarily aggregate virus on the cell surface, effectively reducing the amount of virus released from infected cells. The neuraminidase protein can be divided into nine distinct antigenic subtypes, where there is little cross-protection of antibodies between subtypes. All nine subtypes of neuraminidase protein are commonly found in avian influenza viruses, but only selected subtypes are routinely found in mammalian influenza viruses; for example, only the N1 and N2 subtypes are commonly found in both humans and swine. Even within a subtype, the neuraminidase protein can have a high level of antigenic drift, and vaccination has to specifically be targeted to the circulating strain to give optimal protection. The levels of neuraminidase antibody also appear to be critical for protection, and there is concern that human influenza vaccines do not include enough neuraminidase protein to induce a strong protective antibody response. The neuraminidase protein has also become an important target for antiviral drugs that target sialic acid binding which blocks neuraminidase enzyme activity. Two different antiviral drugs are available and are widely used for the treatment of seasonal influenza in humans, but antiviral resistance appears to be a growing concern for this class of antivirals.
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Both purified expressed proteins and virus-like particles generated in insect cells by recombinant baculoviruses are being explored as potential vaccines for seasonal and pandemic influenza. Clinical trials have suggested that recombinant hemagglutinin vaccines are well tolerated in healthy and elderly adults, that they induce a functional antibody response, and that they provide protection against seasonal influenza in adults. In one trial, a pandemic formulation of H5 vaccine (rH5) induced neutralizing antibody in adults at rates roughly similar to that seen with egg-derived subvirion H5N1 vaccine. Preliminary data suggest that vaccination with the rH5 can also prime for booster responses on revaccination with drifted strains of H5. Recombinant approaches may be extremely valuable in combating future pandemics and further studies of recombinant pandemic vaccines in humans are needed.
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As an attractive alternative to conventional vaccines, DNA vaccines play a critical role in inducing protection against several infectious diseases. In this review, we discuss the advantages that DNA vaccines offer in comparison to conventional protein-based vaccines. We discuss strategies to improve the potency and efficacy of DNA vaccines. Specifically, we focus on the potential use of DNA-based vaccines to elicit broad-spectrum humoral and cellular immunity against influenza virus. Finally, we discuss the advances made in the use of DNA vaccines to prevent avian H5N1 influenza.
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The development of reverse genetics techniques allowing the rescue of influenza virus from plasmid DNA has opened up the possibility of inserting mutations into the genome of this virus for the generation of novel live attenuated influenza virus vaccines. Modifications introduced into the viral NS1 gene via reverse genetics have resulted in attenuated influenza viruses with promising vaccine potential. One of the main functions of the NS1 protein of influenza virus is the inhibition of the innate host type I interferon-mediated antiviral response. Upon viral infection, influenza viruses with modified NS1 genes induce a robust local type I interferon response that limits their replication, resulting in disease attenuation in different animal models. Nevertheless, these viruses can be grown to high titers in cell- and egg-based substrates with deficiencies in the type I IFN system. Intranasal inoculation of mice, pigs, horses, and macaques with NS1-modified influenza virus strains induced robust humoral and cellular immune responses, and generated immune protection against challenge with wild-type virus. This protective response was not limited to homologous strains of influenza viruses, as reduced replication of heterologous strains was also demonstrated in animals vaccinated with NS1-modified viruses, indicating the induction of a broad cross-neutralizing response by these vaccine candidates. The immunogenicity of NS1-modified viruses correlated with enhanced activation of antigen-presenting cells. While further studies on their safety and efficacy are still needed, the results obtained so far indicate that NS1-modified viruses could represent a new generation of improved influenza virus vaccines, and they suggest that modifying viral interferon antagonists in other virus families is a promising strategy for the generation of live attenuated virus vaccines.
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Recent outbreaks of highly pathogenic avian influenza A virus infections (including those of the H5N1 subtype) in poultry and in humans (through contact with infected birds) have raised concerns that a new influenza pandemic will soon occur. Effective vaccines against H5N1 virus are therefore urgently needed. Reverse genetics-based inactivated vaccines have been prepared according to WHO recommendations and licensed in several countries following their assessment in clinical trials. However, the effectiveness of these vaccines in a pandemic is not guaranteed. We must therefore continue to develop alternative pandemic vaccine strategies. Here, we review the current strategies for the development of H5N1 influenza vaccines, as well as some future directions for vaccine development.
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Beginning in Southeast Asia in 2003, a multinational epizootic outbreak of H5N1 highly pathogenic avian influenza (HPAI) was identified in commercial poultry and wild bird species. This lineage, originally identified in Southern China in 1996 and then Hong Kong in 1997, caused severe morbidity and mortality in many bird species, was responsible for considerable economic losses via trade restrictions, and crossed species barriers (including its recovery from human cases). To date, these H5N1 HPAI viruses have been isolated in European, Middle Eastern, and African countries, and are considered endemic in many areas where regulatory control and different production sectors face substantial hurdles in controlling the spread of this disease. While control of avian influenza (AI) virus infections in wild bird populations may not be feasible at this point, control and eradiation of AI from commercial, semicommercial, zoo, pet, and village/backyard birds will be critical to preventing events that could lead to the emergence of epizootic influenza virus. Efficacious vaccines can help reduce disease, viral shedding, and transmission to susceptible cohorts. However, only when vaccines are used in a comprehensive program including biosecurity, education, culling, diagnostics and surveillance can control and eradication be considered achievable goals. In humans, protection against influenza is provided by vaccines that are chosen based on molecular, epidemiologic, and antigenic data. In poultry and other birds, AI vaccines are produced against a specific hemagglutinin subtype of AI, and use is decided by government and state agricultural authorities based on risk and economic considerations, including the potential for trade restrictions. In the current H5N1 HPAI epizootic, vaccines have been used in a variety of avian species as a part of an overall control program to aid in disease management and control.
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Drug delivery to the nasal cavity has been achieved using a variety of systems. Dry powder vaccines offer the advantages of chemical and physical stability in comparison to liquid formulations. An intranasal vaccine can elicit both a local and systemic immune response. Mucoadhesive compounds can extend the residence time for powder formulations on the nasal mucosa, potentially increasing the immune response. Manufacture and characterization of a formulation containing particles of a dry powder vaccine are discussed.
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In this chapter, we will review the development of and clinical experience with the currently licensed seasonal live attenuated influenza vaccines (LAIV) and preclinical studies of H5, H7, and H9 live attenuated pandemic influenza vaccine candidates. Vectored vaccine approaches will not be reviewed in this chapter. Experience with seasonal influenza vaccination has demonstrated the safety and efficacy of LAIV in both children and adults; moreover, cross-protection among antigenically distinct viruses within the same subtype may be induced by LAIV. While clinical studies and further characterization of the immunologic response to avian influenza viruses are still needed, the experience with seasonal LAIV underscores the potential of live attenuated vaccines to play an important role in the event of a pandemic.
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Vaccination will be a critical public health intervention to mitigate the next influenza pandemic. Its effectiveness will depend on preparedness at multiple levels, from the laboratory bench to the population. Here we describe a global approach to ensure that appropriate candidate vaccine viruses are produced, evaluated, and made available to vaccine manufacturers in a timely fashion. This is an integrated activity involving global virologic and epidemiologic surveillance, genetic and antigenic characterization of influenza viruses, pandemic risk assessments, selection of appropriate virus strains for vaccines, production of reassortant viruses by reverse genetics, and finally, analysis of their safety and growth characteristics prior to distribution. These procedures must comply with national and international regulations governing vaccine and environmental safety.
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Influenza vaccines are the mainstay of efforts to reduce the substantial health burden from seasonal influenza. Inactivated influenza vaccines have been available since the 1940s and are administered via intramuscular injection. Inactivated vaccines can be given to anyone six months of age or older. Live attenuated, cold-adapted influenza vaccines (LAIV) were developed in the 1960s but were not licensed in the United States until 2003, and are administered via nasal spray. Both vaccines are trivalent preparations grown in eggs and do not contain adjuvants. LAIV is licensed for use in the United States for healthy nonpregnant persons 2–49 years of age.
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There is an urgent need to develop novel approaches for vaccination against emerging pathogenic avian influenza viruses as a priority for pandemic preparedness. Influenza virus-like particles (VLPs) have been suggested and developed as a new generation of non-egg-based cell culture-derived vaccine candidates against influenza infection. Influenza VLPs are formed by a self-assembly process incorporating structural proteins into budding particles composed of the hemagglutinin (HA), neuraminidase (NA) and M1 proteins, and may include additional influenza proteins such as M2. Animals vaccinated with VLPs were protected from morbidity and mortality resulting from lethal influenza infections. The protective mechanism of influenza VLP vaccines was similar to that of the currently licensed influenza vaccines inducing neutralizing antibodies and hemagglutination inhibition activities. Current studies demonstrate that influenza VLP approaches can be a promising alternative approach to developing a vaccine for pandemic influenza viruses. The first human clinical trial of a recombinant pandemic-like H5N1 influenza VLP vaccine was initiated in July 2007 (Bright et al., unpublished).
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The unprecedented spread of highly pathogenic H5N1 viruses since 1996 has had public health and scientific entities scrambling to prepare for a possible pandemic. Central to many of these efforts has been the development of vaccines. As the viruses have continued to spread, however, they have continued to diversify genetically, complicating vaccine strain selection. The key to successful vaccine design is understanding the cross-reactivity between these genetically distinct H5N1 strains. Studies conducted to date show encouraging amounts of cross-reaction and cross-protection between various H5N1 strains, although our ability to predict one based upon the other is poor. Understanding the targets and mechanisms behind this cross-protection should be a key focus of pandemic preparedness.
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The antiquated system used to manufacture the currently licensed inactivated influenza virus vaccines would not be adequate during an influenza virus pandemic. There is currently a search for vaccines that can be developed faster and provide superior, long-lasting immunity to influenza virus as well as other highly pathogenic viruses and bacteria. Recombinant vectors provide a safe and effective method to elicit a strong immune response to a foreign protein or epitope. This review explores the advantages and limitations of several different vectors that are currently being tested, and highlights some of the newer viruses being used as recombinant vectors.
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Since their compositions remain uncertain, universal pandemic vaccines are yet to be created. They would aim to protect globally against pandemic influenza viruses that have not yet evolved. Thus they differ from seasonal vaccines to influenza virus, which are updated annually in spring to incorporate the latest circulating viruses, and are then produced and delivered before the peak influenza season starts in late fall and winter. The efficacy of seasonal vaccines is linked to their ability to induce virus-neutralizing antibodies, which provide subtype-specific protection against influenza A viruses. If pandemic vaccines were designed to resemble current vaccines in terms of composition and mode of action, they would have to be developed, tested, and mass-produced after the onset of a pandemic, once the causative virus had been identified. The logistic problems of generating a pandemic vaccine from scratch, conducting preclinical testing, and producing billions of doses within a few months for global distribution are enormous and may well be insurmountable. Alternatively, the scientific community could step up efforts to generate a universal vaccine against influenza A viruses that provides broadly cross-reactive protection through the induction of antibodies or T cells to conserved regions of the virus.
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The use of adjuvants is being explored as a means of improving vaccine immunogenicity. This is particularly important for the development of vaccines against potential pandemic influenza virus strains. Adjuvants act by prolonging the exposure time of antigen to the immune system, enhancing the delivery of antigen to antigen-presenting cells, or providing immunostimulatory signals that potentiate the immune response. Aluminum salts are the only licensed adjuvant in the United States, but the combination of these salts with inactivated influenza A/H5N1 antigens has had little effect on seroresponses. Several oil-in-water adjuvants, including MF59 and AS03, have significantly enhanced immune responses in healthy adult vaccine recipients to inactivated influenza A/H5N1. Additional studies are needed in vulnerable populations (younger and elderly persons, pregnant women, and immunocompromised patients) to confirm the safety and enhanced immunogenicity of these promising formulations. A number of other adjuvants are under investigation to evaluate their ability to improve the immunogenicity of inactivated vaccines targeting influenza A/H5N1.
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Transcutaneous immunization (TCI) is a novel vaccination route involving the topical application of vaccine antigens on the skin. The skin is an attractive site for vaccination because it is rich in various antigen-capturing immune cells. The outer skin barrier can be overcome through the use of mild chemical and/or physical treatments, including ethanol-water hydration and stripping, which allows for large vaccine molecules or even particulate antigens to gain access to the skin's immune cells. The use of toxin adjuvants such as cholera or heat-labile toxins was demonstrated to enhance the immunogenicity of vaccine antigens, probably due to their stimulatory effects on immune cells. Oleic acid or retinoic acid, known as permeation enhancers or immune modulators, were found to increase immune responses to inactivated whole-influenza viral vaccines. The further development of more effective delivery systems and nontoxic adjuvants is needed to enhance the efficacy of this approach to vaccination.
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A number of protective immune functions decline with age along with physiological and anatomical changes, contributing to the increased susceptibility of older adults to infectious diseases and suboptimal protective immune responses to vaccination. Influenza vaccination is the most cost-effective strategy to prevent complications from influenza viral infections; however, the immunogenicity and effectiveness of currently licensed vaccines in the United States is about 30-50% in preventing complications arising from influenza and preventing death from all causes during winter months in older adults. Hence, it is crucial to understand the molecular mechanisms that lead to immune dysfunction as a function of age so that appropriate strategies can be developed to enhance the disease resistance and immunogenicity of preventive vaccines, including influenza vaccines, for the older adult population.
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The emergence of influenza A/H5N1 viruses in Asia has raised concerns about their potential to cause pandemic disease. Because vaccination is the primary strategy for the prevention of influenza, efforts are in progress to develop safe and immunogenic vaccines against these viruses and other potential pandemic influenza strains. Results of initial studies indicated that subunit influenza A/H5N1virus vaccines were poorly immunogenic, and that high dosages were needed to induce seroresponses in the majority of subjects. Addition of aluminum-containing adjuvants resulted in variable effects on the immunogenicity of H5 vaccines, but in general, clinically meaningful effects have not been observed. Intradermal immunization was not associated with significant enhancement in one study. More recent studies indicate that oil-in-water adjuvants significantly enhance immune responses when compared with nonadjuvanted preparations containing the same dosage of H5 or H9 hemagglutinin. In addition, these formulations elicit higher levels of cross-reactive antibodies vs. different H5N1 clades. Several whole-virus vaccines have been demonstrated to stimulate high frequencies of responses at relatively low dosages; however, direct comparisons with subunit vaccines have not been made. Finally, candidate live attenuated vaccines are under evaluation in clinical trials. The results of these and future trials will help to identify formulations and immunization regimens for various populations, and will better prepare us to address the threat of both pandemic and interpandemic influenza.
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With over 409 human cases of avian influenza and over 256 deaths worldwide resulting from infection with avian influenza (H5N1), an influenza pandemic is still a real threat, especially with H5N1 continuing to evolve into antigenically distinct clades. The Food and Drug Administration (FDA) along with other national regulatory authorities (NRAs) recognize the important role that safe and effective vaccines will play in protecting the public health from the threat of an influenza pandemic. The challenges to the FDA and other NRAs are significant as regulatory agencies pursue the development of new scientific and regulatory criteria to evaluate vaccines against pandemic influenza strains for licensure. To this end, the FDA is actively utilizing current regulatory processes such as accelerated approval and priority review as well as developing the regulatory pathways needed to speed the availability of vaccines against pandemic influenza. In May of 2007, the FDA issued two final guidance documents, one describing the clinical data recommended to support the licensure of annual influenza vaccines, and the other describing the clinical data recommended to support the licensure of pandemic influenza vaccines. These guidances contain specific approaches outlined by the FDA to assist manufacturers in developing new vaccines to increase the supply of safe and effective influenza vaccines for both annual and pandemic use. In this article we define the nomenclature "pandemic" and "prepandemic," describe the regulatory pathway for licensing new influenza vaccines for pandemic and prepandemic use, and outline considerations for evaluating pandemic/prepandemic vaccines that have been formulated using new approaches such as cell culture and non-aluminum salt adjuvants.
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The global need for a pandemic influenza vaccine is large. High-income countries have stated their intent to provide universal access for pandemic influenza vaccine to their populations. Assuming that a two-dose schedule would be needed, providing universal coverage globally would represent approximately 6.5 billion two-dose courses or 13 billion doses. In the best case scenario, should an outbreak of pandemic influenza occur in the near term, using H5N1 as a proxy for the pandemic virus, the total available doses for the global population within six months of an out break would be only 1.2 billion courses or 2.4 billion doses. In addition, current stockpiles of pandemic influenza vaccine are limited. However, promising developments are occurring with respect to global capacity, technological innovation, and global conviction that offer potential solutions to the problem of pandemic influenza vaccine supply for the world's population.
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Biotechnology–and aerosol delivery specifically–is beginning to blur the line between solutions and threats. Could a cure for diabetes and a dangerous pathogen be delivered in the same way? Such a scenario isn't far off.
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Currently, the majority of vaccines is administered parenterally by injection and is designed to induce protective immunity mainly through the induction of circulating antibodies. However, it is likely that some vaccines could be more effective if they were administered via mucosal routes. In contrast to parenteral delivery, mucosal immunization offers the possibility to induce immune responses directly at the sites where most pathogens initially infect. Hence, mucosal immunity could act as a first line of defense and, if systemic immunity is also present, could offer two layers of host protection. Moreover, needle-free vaccine administration has many potential additional advantages, including the potential to improve safety and increase patient compliance, with the potential for self-administration. Mucosal vaccine delivery is likely to progress over the next decade as the currently limited knowledge of the molecular mechanisms for the induction of mucosal immunity is expanded. A key challenge will be the design of efficacious and safe mucosal vaccines, with the stability of recombinant antigens after mucosal administration remaining a significant challenge. The combination of a broad panel of adjuvants and delivery technologies holds tremendous promise for effective, safe, needle-free vaccines, and the area is likely set for rapid advances over the next decade. © Springer Science+Business Media New York 2014. All rights are reserved.
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This paper will present an overview of advances in science and technology in some of the key areas of the life sciences that have particular implications for biosecurity and the biological weapons prohibition regime as States Parties to the BWC approach its 7th Review Conference in December 2011. It focuses on the areas of functional genomics, synthetic biology, systems biology, and targeted delivery systems, which have advanced significantly in recent years. In addition, it will briefly touch upon the issue of mid spectrum agents which are often overlooked and in relation to which control or prevention efforts are far from satisfactory.
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In this article, Timothy Sullivan, President, Chief Executive Officer and Founder of Mystic Pharmaceuticals, provides background information on the drivers for the development of stable, nasally administered vaccines, which can be manufactured and deployed rapidly, and describes the drug delivery devices and dosage forms under development by Mystic, as well as the company's rapid form-fill-seal manufacturing processes.
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Aerosol drug delivery to the lungs has long been the route of choice for the treatment of respiratory diseases, including asthma and chronic obstructive airway disease. Metered dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers have been employed to successfully deliver a wide range of pharmaceuticals principally to the lungs for local action. This article focuses on aerosol drug delivery devices, their development, and future prospects for pulmonary administration. Keywords: aerosol drug delivery; metered dose inhalers (MDIs); dry powder inhalers (DPIs); nebulizers
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Respiratory syncytial virus (RSV) is the most important cause, throughout the world, of severe viral lower respiratory tract illness in young children. Antibodies are known to mediate resistance to RSV infection and illness. We have isolated a number of human monoclonal Fab fragments to RSV F glycoprotein from a combinatorial antibody library expressed on the surface of phage. One of these neutralized a wide range of virus isolates, 10 subgroup A and 9 subgroup B isolates, with a titer (60% neutralization) of approximately 0.1-1.0 micrograms/ml. Another Fab neutralized diverse isolates at a concentration somewhat higher. These human Fab fragments show great promise for use in the prophylaxis or therapy of serious RSV lower respiratory tract disease. For intramuscular or intravenous administration, whole antibodies will be required, whereas for aerosol application, F(ab')2 or Fab fragments may suffice.
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In an attempt to evaluate the level of attenuation of live parainfluenza type 3 virus (PIV3) vaccine candidates, we compared the responses of partially immune adult volunteers inoculated intranasally with 10(6) to 10(7) 50% tissue culture infective dose (TCID50) of bovine PIV3 (n = 18) or cold-adapted (ca) PIV3 (n = 37) with those of 28 adults administered 10(6) to 10(7) TCID50 of wild-type PIV3. The candidate vaccine viruses and the wild-type virus were avirulent and poorly infectious for these adults even though all of them had a low level of nasal antibodies to PIV3. To determine whether the ca PIV3 was attenuated, we then administered 10(4) TCID50 of ca PIV3 (cold-passage 12) or wild-type PIV3 intranasally and intratracheally to two fully susceptible chimpanzees, respectively, and challenged the four primates with wild-type virus 1 month later. Compared with wild-type virus, which caused upper respiratory tract illness, the ca PIV3 was highly attenuated and manifested a 500-fold reduction in virus replication in both the upper and lower respiratory tracts of the two immunized animals. Despite restriction of virus replication, infection with ca PIV3 conferred a high level of protective immunity against challenge with wild-type virus. The ca PIV3 which had been passaged 12 times at 20 degrees C did not retain its ts phenotype. These findings indicate that ca PIV3 may be a promising vaccine candidate for human beings if a passage level can be identified that is genetically stable, satisfactorily attenuated, and immunogenic.
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In 1915, Greenwood and Yule noted that for valid vaccine efficacy studies, exposure to infection in the vaccinated and the unvaccinated must be equal (Proc R Soc Med 1915;8(part 2):113-94). The direct effect of a vaccine, however, needs to be defined by the protection it confers given a specific amount of exposure to infection, not just a comparable exposure. In this paper, two classes of parameters are distinguished along lines differing from the conventional distinction between efficacy and effectiveness. Efficacy parameters attempt to control for exposure to infection and represent direct effects on individuals. Direct effectiveness parameters represent a mixture of direct effects on individuals and indirect effects in the population.
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The pathogenesis of herpes simplex virus encephalitis and myelitis was studied in suckling mice using routine titration procedures and fluorescent antibody staining for the identification of infected cells. After intracerebral inoculation virus was shown to disperse rapidly in the cerebrospinal fluid (CSF), multiply in meninges and ependyma, and then invade the underlying parenchyma infecting both neurons and glia. Following extraneural inoculation virus gained access to the central nervous system (CNS) by both hematogenous and neural pathways. After intraperitoneal and intranasal inoculation virus was found to multiply in viscera and produce viremia; foci of CNS infection then developed around small cerebral vessels. After subcutaneous and intranasal inoculation neural spread of virus was demonstrated along corresponding peripheral and cranial nerves. This spread resulted from the centripetal infection of endoneural cells (Schwann cells and fibroblasts). Antigen was not found in axons even after infection of the corresponding ganglion cell perikaryon. Subsequent spread within the CNS was unrelated to neural tracts, and there was no evidence of axonal spread of virus in the host-virus system studied. These findings are discussed in relation to previous and current theories of the viral "blood-brain barrier" and neural pathways of infection.
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Tetanus toxoid was incorporated into liposomes of equimolar concentrations of distearoyl phosphadylcholine (DSPC) and cholesterol. We investigated the non-parenteral delivery of free or liposome entrapped tetanus toxoid to guinea pigs and measured the subsequent IgG anti-tetanus-antibody response, using an ELISA. Liposome formulation significantly improved the immune response when compared to the free antigen when delivered via the nasal, oral and i.m. routes. However, 10 × concentration of tetanus toxoid entrapped in DSPC introduced mucosally (nasally and orally) was necessary to produce an IgG antibody titre similar to those obtained via the i.m. delivery. This study suggests that liposomes, administered through the oral and nasal routes, have considerable potential as mucosal adjuvants and warrant further investigation.
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1. The strain HFEM of herpes simplex virus is highly virulent for the 5-week-old mouse when inoculated intracerebrally; the LD50 and the ID50 both being close to the egg infectious unit. It is also virulent when given intraspinally. 2. When inoculated peripherally it seldom causes nervous symptoms in the normal mouse but regularly does so if inoculated into skin which has previously been given a subcutaneous injection of 10% sodium chloride. 3. After intradermal inoculation of pretreated mice with strain HFEM, the paralysis is preceded by the appearance of infective virus in the blood, the sciatic nerve and the central nervous system. Invasion of the central nervous system is prevented by interruption of the local peripheral nerve. 4. There is no evidence that virus enters the central nervous system by way of the lymphatics or by direct extension through the tissues. 5. After intravenous inoculation virus does not invade the central nervous system unless ( a ) massive inocula are used or ( b ) the brain is traumatized by injecting sterile saline. After peripheral inoculation insufficient virus to infect even traumatized brain seems to circulate in the cerebral vessels. Paralysis and invasion of the central nervous system are not prevented by circulating neutralizing antibody given 18 hours after inoculation. It therefore appears that invasion of the central nervous system takes place only by way of the peripheral nerve.
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Oral or aerosol administration of a live trivalent Pasteurella anatipestifer (PA) vaccine (sero‐types 1, 2 and 5) gave significant protection against homologous challenges in White Pekin ducklings. Vaccination of one‐day‐old ducklings by either method provided protection for at least 42 days of age (last challenge). The vaccine did not cause any untoward signs or mortality in one‐day‐old ducklings exposed to ten times the recommended dose. The vaccine strains did not revert to virulence on 10 back‐passages. However, they were reisolated from tracheas and sinuses of the contact‐exposed ducklings which were also resistant to challenge with homologous serotype. Feeding of chlortetracycline (0.044%) or sulphadime‐thoxine‐ormetoprim (0.02%) for first 2 weeks of age had no adverse effect on efficacy of the vaccine. The vaccine was found to be both safe and efficacious in field trials in which one‐day‐old ducklings were exposed by aerosol in the hatcher.
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Chickens were vaccinated with inactivated Newcastle disease (ND) vaccine by the oculonasal, intratracheal (it) or the aerosol route and immunity was measured by determination of haemagglutinating inhibiting (HI) antibodies and survival following challenge. Dose-response to various vaccination schedules was studied in birds of various ages with or without maternal antibodies. IT application induced a stronger response than oculonasal application. A single application with a vaccine dose of 1 to 10 mg allantoic dry matter by the it or the aerosol route resulted in moderate titres in adult birds, while a dose of 0.1 mg still had a priming effect. In one-day-old SPF chicks doses of 1 to 10mg given with adjuvant induced only low titres but protection was present following challenge at 3 to 4 weeks of age, while 0.2 mg had no effect. Maternal antibodies interfered with vaccine efficacy. A more economical use of the vaccine and a better immune response was obtained by repeated vaccination. Twice weekly aerosol exposure, with a dose of about 0.2 mg, induced HI titres of 8 to 9 in 9-week-old hens after four exposures. Five aerosol vaccinations with doses of about 0.1 mg but with adjuvant were effective in young chicks with or without maternal antibodies. In SPF chicks HI titres of 8 to 9 were achieved, while broilers with high levels of maternal antibodies were protected completely against morbidity following challenge. It is concluded that, although repeated aerosol vaccination with inactivated ND virus is effective, it is not economical at present.
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A consideration of the published works dealing with the behavior of herpes simplex virus in nervous system tissue of man and animals and a review of the recent work demonstrating the capability for this virus to remain latent in sensory ganglia for prolonged periods both in animals and in humans suggests that sensory neurons may, because of some special properties, provide the essential milieu for residence of the virus for prolonged periods. They may constitute the reservoir for recurrent herpes simplex virus infections, most notably the recurrent oral or genital ulceration. The role of latent herpes simplex virus within nervous system tissue in producing either acute episodes of encephalitis in man or serving as a reservoir of virus which may in other tissues manifest transforming potential or other disease processes remains unknown and is the subject for future investigation. (100 references.)
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Respiratory syncytial virus ts-1 is a live attenuated experimental vaccine which was administered intranasally to 25 infants 11 to 19 months of age. Clinical evaluation was carried out following a controlled, double-blind protocol which eliminated observer bias, assessed intercurrent illness, and was designed to detect virus transmission. At the low dose of virus of virus used (100 TCID50) 8 of the 25 recipients were successfully infected with RS virus ts-1 as determined by virus shedding or antibody response.
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Herpes simplex virus encephalitis tends to localize to the temporal and orbitofrontal lobes, giving characteristic clinical and pathological findings. Since the virus remains latent in the trigeminal ganglia, we postulate that this localization may be explained by reactivated virus spreading along the fifth nerve fibers, which innervate basal meninges of the anterior and middle fossae.
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Many drugs of the future will be therapeutically active peptides and proteins developed through recombinant-DNA technology. A major factor limiting their exploitation is the current lack of appropriate non-parenteral delivery systems. Nasal systems incorporating absorption enhancers may provide a convenient, efficient means of administering protein and peptide therapeutics.
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It is a special pleasure for me to participate in today's symposium, in honor of my cousin Saul Krugman's 80th birthday and to celebrate his important contributions to our knowledge of infectious diseases. It so happens that I have also spent my life in the pursuit of knowledge of infectious diseases, and yet, despite our close family relationship—he is the son of my mother's brother—our paths rarely crossed until he was 35 years old. It was then that Saul, without any special training in bacteriology, virology, immunology, or pathology, decided to spend his life in academic pediatrics and infectious diseases. Was there any link between Saul's career in infectious diseases and my own, which began 64 years ago? In October 1946, after 5 years as a flight surgeon and a 6 months' residency at the Willard Parker Hospital, then the center for all the horrible communicable diseases of children in New York City, Saul applied for a residency in pediatrics. But there were no vacancies for this 35-year-old World War II veteran. It was then that Saul came to Cincinnati to seek my advice. In 1940, after a pediatric residency at Hopkins, Dr Robert Ward came to my laboratory to work on polio and other viruses. In 1943, when I left Cincinnati to join the Army, Robbie Ward was not accepted by the Army because of an old tuberculous lesion acquired on the wards of the Hopkins Harriet Lane Hospital, and he joined John R. Paul at Yale to work on polio and hepatitis.
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The avirulent Newcastle disease virus strain designated NDV-6/10, selected by B. Lomniczi at the Veterinary Medical Research Institute, Hungarian Academy of Sciences, is completely safe for day-old chickens by aerosol vaccination. Aerosol immunization using the Hungarian-made MASTERDROP generator (particle size: maximum 7 microns) caused no vaccination reactions among 206,000 chickens with different maternal antibody levels. Other vaccines given simultaneously did not significantly affect the protection elicited against Newcastle disease (ND). Almost 100% and 90% of the aerosolized chickens survived subcutaneous challenge with 10(6) LD50 NDV at 30 and 50 days old, respectively. A single immunization is sufficient for broilers; however, parent flocks should be revaccinated at 7 so 8 weeks old.
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Mucosal immunization of mice with purified Bordetella pertussis filamentous hemagglutinin (FHA), by either the respiratory or the gut route, was found to protect against B. pertussis infection of the trachea and lungs. Intranasal immunization of BALB/c and (C57BL/6 x C3H/HeN)F1 adult female mice with FHA prior to B. pertussis aerosol challenge resulted in a 2 to 3 log reduction in number of bacteria recovered from the lungs and the tracheas of immunized mice in comparison to unimmunized controls. Intraduodenal immunization of adult mice with FHA before infection also resulted in approximately a 2 log reduction in the recovery of bacteria from the lungs and the tracheas of immunized mice in comparison to unimmunized controls. Immunoglobulin A and immunoglobulin G anti-FHA were both detected in bronchoalveolar lavage fluids of mucosally immunized mice. Limiting dilution analysis revealed a 60-fold increase in the frequency of FHA-specific B cells isolated from the lungs of mice immunized intranasally with FHA in comparison to unimmunized control mice. These data suggest that both gut and respiratory mucosal immunization with a major adhesin of B. pertussis generates a specific immune response in the respiratory tract that may serve as one means of mitigating subsequent B. pertussis respiratory infection.
Article
An easily administered and safe vaccine is required to produce the herd immunity necessary to control influenza epidemics worldwide. A commercial quadrivalent inactivated split influenza vaccine was administered intranasally in aerosol form to a group of 46 volunteers; other groups were given the same vaccine subcutaneously and saline intranasally. The results show that mucosal stimulation via intranasal vaccination resulted in a marked increase in local HA-specific IgA antibodies, and that this stimulation was necessary for serum HA-specific IgA responses. Serum HA-specific IgA antibody levels can be used as indicators of local antigenic stimulation, providing a method for evaluating potency and antigenicity in humans of intranasal influenza vaccine. This vaccination route shows much promise for the future.
Article
Day-old chickens were given a single fowlpox virus vaccination (strain HP201) either via the aerosol or wing-web route. Both methods induced protective immunity against a wing-web or intravenous challenge with virulent fowlpox virus at 47 days old, although high titred virus preparations were required for successful aerosol vaccination. However, no clinical signs of infection were observed as a result of aerosol vaccination even if invasive strains of Escherichia coli were administered simultaneously. The use of aerosol fowlpox virus vaccination of day-old chicks has been shown to be a possible means of mass vaccination and could be applied to the use of fowlpox virus in recombinant vaccines.
Article
One-day-old chicks with maternally derived antibodies were vaccinated against infectious bronchitis (IB) with 3000 EID50 of the IB vaccine virus designated H120. The degree of protection induced by intranasal-eye drop (IE) vaccination was compared to that achieved by spray (S) vaccination. The protection afforded by vaccination was monitored by intratracheal challenge with IBV strain M-41 (clinical signs, ciliary activity in tracheal explants, virus isolation) and by serological tests (ovoneutralization, microneutralization in cell culture, haemagglutination inhibition (HI) test, ELISA). Intranasal-eye drop vaccination provided protection against intratracheal challenge. Immunity developed around 31 days of age. Spray vaccination failed to give protection against challenge by the same route. No difference was demonstrable in effectiveness between the two routes of vaccination by serological tests. No elevation of the antibody level occurred in either group. The level of maternally derived antibodies declined with age.
Article
Increased awareness of the fact that the mucosal membranes are the portals of entry for the majority of infectious agents, and that antibodies in external secretions often correlate better with protection than do corresponding antibodies in serum, has prompted many recent studies aimed at the selective induction of antibodies in mucosal secretions. The recent development of novel technologies (expression of antigens in various microbial vectors that colonize mucosal surfaces and incorporation of antigens in biodegradable microspheres) indicate that the goal of vaccination with enhanced induction of both mucosal and systemic immune responses is attainable.
Article
Coarse-spray (CS) administration of a commercial S1133 reovirus vaccine in chickens for prevention of clinical viral tenosynovitis (VT) infection was evaluated. In Expt. 1, one-day-old specific-pathogen-free (SPF) white leghorns were vaccinated with a combination of reovirus, Newcastle disease (ND), and infectious bronchitis (IB) vaccines by CS and infectious bursal disease vaccine by the subcutaneous (SQ) route. In Expt. 2, one-day-old commercial broilers were vaccinated by CS with reovirus vaccine and Marek's disease (MD) vaccine by SQ. In Expt. 3, one-day-old commercial broilers received reovirus vaccine in combination with ND-IB vaccines at 1 day of age by CS and MD vaccine by SQ. Some birds received an initial or second vaccination at 7 days of age by CS or the drinking-water (DW) route. Birds vaccinated by CS at 1 day of age with reovirus vaccine did not produce circulating virus-neutralizing antibody against reovirus, although they had resistance to VT infection. In contrast, initial or booster vaccination at 7 days of age by CS or DW resulted in an antibody response and greater resistance to challenge than did CS vaccination at 1 day of age. There was no difference in efficacy between CS and DW routes at 7 days of age. The reovirus vaccine did not interfere with other vaccines as measured by serologic (ND-IB-IBD) or challenge (MD) studies.
Article
Measles, which is still killing about two million children a year in poor countries, was mostly eliminated within two to three months after the conclusion of a special, national mass vaccination campaign in which all children of a selected age group received measles vaccine subcutaneously during a period of days to months, regardless of a history of previous vaccination or measles. This strategy was tested in the Dominican Republic in 1985, in Cuba in 1986–87, and in the State of São Paulo, Brazil May 11 – June 10, 1987. Subsequent control was maintained by different procedures in the three states. A simple, rapid indirect immunoflueorescent test for IgM measles antibody, used in Greater São Paulo, was more efficient in confirming concurrent infection with measles virus than the hemagglutination inhibition test for IgG antibody, and only one blood specimen taken during the course of the rash was needed to confirm the etiologic diagnosis in 97.5% of 240 cases confirmed by IgM. In Greater São Paulo and Cuba, it was found that over 90% of the small number of suspect measles cases reported during the first year after the mass campaign, were not caused by measles virus. The cost of disposable syringes and needles in the State of São Paulo, where 8,565,230 children were vaccinated in 10,527 centers in 30 days, was U.S. $2,057,753 or 63% of the total. Immunization by aerosol could have vaccinated this number of children more easily and effectively in one day if each of the vaccination centers had been supplied with one plastic foot or hand pressure pump and nebulizer at a cost of only about U.S. $300,000.
Article
In view of the measles epidemic that affected the country, a resolution was taken to enlarge the extent of vaccination range in school age groups, which were the most affected in such epidemic. The vaccination with the aerosol method, allowed the optimization of the vaccine, the application time, and the human resources. There were 208,045 scholastics vaccinated in Tabasco, a survey was performed in the jurisdiction of Jalpa de Méndez with 6,738 vaccinated children in order to find out the postvaccination reactions a week after the vaccine was inhaled. It was found in 1,844 children, that there were different signs and symptoms that did not represent a risk for the application of the aerosol method.
Article
The virulence and immunogenicity of a wild-type respiratory syncytial (RS) virus together with four temperature sensitive (ts) mutants derived from this isolate were tested by intranasal inoculation into adult volunteers. Resistance to challenge correlated with neutralizing antibody titres in nasal secretions and to a lesser extent in serum. All ts mutants were reduced in virulence. Mutant ts1B caused mild or asymptomatic infections yet induced antibody responses comparable with wild-type RS virus. Ts1B might be developed further to produce a live-virus vaccine.
Article
Intranasally administered alpha/beta interferon blocked extension of the coronavirus, mouse hepatitis virus, strain JHM (MHV-JHM), from the nose to the brain of BALB/cByJ mice following intranasal inoculation with the virus. Two hundred units of alpha/beta interferon were administered intranasally to BALB/cByJ mice daily over a five day period. The mice were exposed intranasally to 10(3) median tissue culture infectious doses of MHV-JHM on the third day of interferon treatment. Two days after virus exposure, the proportion of mice with MHV in nasal turbinates was reduced from 10 of 10 in the untreated group to 7 of 10 in the interferon-treated group, and mean titers in virus-containing noses were lower in the interferon-treated group. Five days after virus exposure, the proportion of mice with infectious virus in the brain was significantly lower in the interferon-treated group (1 of 10 mice) than in the untreated group (10 of 10 mice). Systemic infection, as measured by presence and concentration of virus in the spleen, was not affected by intranasal interferon treatment. These results suggest that intranasally administered interferon protects against local extension of MHV-JHM from nose to brain, but not against dissemination of virus to other organs, such as the spleen.
Article
Perkins, J. C (Lab. Infectious Diseases, NIAID, NIH, Bethesda, Md. 20014), D. N. Tucker, H. L S. Knopf, R. P. Wenzel, R. B. Homick, A. Z. Kapikian and R. M. Qianock. Evidence for protective effect of an inactivated rhinovirus vacdne administered by the nasal route. Amer. L Epid., 1969, 90: 319-326.-The antigenidty and protective effect of an inactivated rhinovirus type 13 vacdne administered intranasally (IN) were evaluated in adult male volunteers. After IN vacdnation, 14 of 17 vaccinees developed a fourfold or greater rise in nasal and/or serum antibody. A significant protective effect of the IN vacdne was seen when the men were challenged with 101.7-102.5 TCD50 of type 13 virus-11 of 13 seronegative controls became ill while only 4 of 12 vaccinees developed illness (p < 0.05).
Article
The antibody response was compared in 40 volunteers who were immunized with parainfluenza Type 2 vaccine, either subcutaneously or by aerosol, and in 16 controls. The neutralizing-antibody response in respiratory secretions was of greater magnitude in the aerosol group than in the other groups. In both the aerosol and the subcutaneous groups there was a significant rise in serum antibody. The respiratory-secretion antibody was found in the IgA class.
Article
Soluble tetanus toxoid given as an aerosol to human volunteers led to an increase in serum antibody titers comparable to that resulting from conventional subcutaneous administration, thus suggesting that tetanus toxoid booster immunization can be administered by aerosol in man. The results also show that an antigen given by fine particle aerosol can stimulate the production of high levels of serum antibody. No increase in the titer of nasal antibody was demonstrated. Sputum antibody titers, however, were found to increase significantly in the persons who received aerosolized vaccine, which demonstrates that secretory antibody was produced in response to an antigen that normally does not enter the respiratory tract.
Article
Electron microscopic examination of mouse brains infected with Semliki Forest virus (SFV) disclosed two major pathways of virion maturation not previously demonstrated in neurons: (1) budding of 28–30 mμ virus cores through the cell surface (plasmalemma); (2) budding of virus cores into cytoplasmic vacuoles and cisternae of the Golgi membrane complex or endoplasmic reticulum. In regions of advanced neuronal infection, virus cores accumulated in large numbers and attached to the limiting membranes of type II cytopathic vacuoles (CPV-II), some of which appeared to derive from the endoplasmic reticulum. Transmigration of virus cores from cytomembrane assembly areas to sites of envelopment at the plasmalemma was evidenced by the presence of virus cores and surface-budding virions in neuronal processes. Axoplasmic transport of virus cores may thus be a factor in spread of arbovirus infections. Intracytoplasmic vacuoles enclosing membranous vesicles of 60–70-mμ diameter were identified in regions of early infection; they corresponded to the type I cytopathic vacuoles (CPV-I) recently observed in tissue cultures and associated with viral RNA replication. Unusual cytomembrane proliferations, described as a “microtubular reticulum” developed regularly in the advanced stages of intracellular SFV infection and aggregates of 30 mμ straight tubules with an electron-dense matrix occaisonally accumulated in close proximity. The ultrastructural findings in SFV-infected neurons correlated closely with electron microscopic and biochemical studies of mesenchymal cell cultures, and indicate broad similarities in the maturation sequence of Group A arboviruses.
Article
Experiments were conducted to examine the aerosol stability and respiratory infectivity of Japanese B encephalitis virus. At 75 degrees F (about 24 degrees C), survival of the virus as aerosol was inversely related to relative humidity. After correction for physical decay, the mean virus half-lives of the virus were 28, 38, and 62 min at relative humiditis of 80, 55, and 30%, respectively. Virus recoveries as aerosol at 4 min aftr dissemination generally exceeded the theoretical limit of 100%, based on the amount disseminated, to suggest that the process of dissemination operated to deagglomerate or release bound virus from the tissue cells in suspension. Swiss-ICR mice and golden Syrian hamsters were highly susceptible to lethal infections after respiratory challenge. Hartley strain guinea pigs and Fisher-Dunning rats, although infected, based on seroconversion observations, survived the infections. Deaths occurred in squirrel monkeys only after exposure to a high aerosol dose of virus (10(6.0) plaque-forming units). Studies of the virus concentration dynamics and histopathological findings in mouse tissues after aerosol challenge supported a hypothesis for direct transport of virus across the foramina of the cribriform plate to the tissues of the central nervous system to produce primary encephalitis.
Article
The immune response is not monolithic. The phenotype of immunity is modulated by the range of environments that lymphocytes experience as they passage through, or lodge for a time in, both secondary lymphoid tissue and other organ systems. Although we are constrained to think in terms of the homogeneity characteristic of the tissue culture flask, the cellular events in particular in vivo sites can vary considerably. The profiles found for accessible "windows" such as the blood, tonsil, or spleen do not necessarily reflect the totality of the host response. The theme of anatomically related divergence in the effector and memory phases of immunity is developed here, using examples from experiments with viruses.
Article
Non-ionic excipients, having different lipophilicity, were compared for their selection of immunological response in different organs and biological fluids. In order to express the lipophilicity of the formulation, the balance between the size and strength of the hydrophilic and lipophilic groups was used, called the hydrophile-lipophile balance (HLB) value. Mice were immunized and boosted intranasally with diphtheria toxoid, and samples were taken from the blood, spleen, nasal wash, lungs, saliva, stomach, duodenum, jejunum and the skin. In general, formulations which were highly hydrophilic and highly lipophilic were not able to augment the immunological response markedly (except for IgA). Formulations having intermediate HLB values, e.g. around 9.0, stimulated both IgG1 and IgG2a production, where the HLB = 5.5 formulation seemed to stimulate mainly IgG2b and IgG3 antibody production. On the other hand, comparing the IgA concentration in various samples with respective IgG level, increasing HLB value seems to augment the production of mainly IgA antibodies. The results indicate that the antibody isotypes may be controlled, using variations in the hydrophile-lipophile balance value.