Next Article in Journal
Cost-Effectiveness of Pertussis Vaccination Schedule in Israel
Next Article in Special Issue
African Trypanosomosis Obliterates DTPa Vaccine-Induced Functional Memory So That Post-Treatment Bordetella pertussis Challenge Fails to Trigger a Protective Recall Response
Previous Article in Journal
Comparison and Analysis of Neutralizing Antibody Levels in Serum after Inoculating with SARS-CoV-2, MERS-CoV, or SARS-CoV Vaccines in Humans
Previous Article in Special Issue
Mapping Global Prevalence of Acinetobacter baumannii and Recent Vaccine Development to Tackle It
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Intranasal Vaccine Delivery Technology for Respiratory Tract Disease Application with a Special Emphasis on Pneumococcal Disease

Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA
Department of Microbiology and Immunology, University at Buffalo, The State University of New York, Buffalo, NY 14203, USA
Author to whom correspondence should be addressed.
Vaccines 2021, 9(6), 589;
Received: 16 April 2021 / Revised: 17 May 2021 / Accepted: 22 May 2021 / Published: 2 June 2021
(This article belongs to the Special Issue Advances in Vaccine Development)


This mini-review will cover recent trends in intranasal (IN) vaccine delivery as it relates to applications for respiratory tract diseases. The logic and rationale for IN vaccine delivery will be compared to methods and applications accompanying this particular administration route. In addition, we will focus extended discussion on the potential role of IN vaccination in the context of respiratory tract diseases, with a special emphasis on pneumococcal disease. Here, elements of this disease, including its prevalence and impact upon the elderly population, will be viewed from the standpoint of improving health outcomes through vaccine design and delivery technology and how IN administration can play a role in such efforts.

1. Introduction

Respiratory tract infectious diseases are ubiquitous due to the airways being the most accessible route to bodily entry. Subsequent infections of the ears, nose, throat, and lungs produce a range of symptoms associated with both viral and bacterial pathogens [1,2,3,4]. Such illnesses are also readily transmissible via aerosolization [5].
Primary examples of respiratory tract diseases include the yearly occurrences of influenza, pneumonia, and the common cold [5,6]. In particular, secondary bacterial pneumonia (commonly triggered by influenza co-infection) can have devastating impacts on the very young and elderly populations, with the resulting illness highlighting synergy between bacterial and viral pathogens [6,7,8,9,10]. Of course, the events of 2020 highlight the continued emergence of coronaviruses into the public perception of respiratory tract diseases.
Various therapies over the years have been applied and tested for respiratory tract diseases, with an emergence of prophylactic options for both viral and bacterial infectious agents [11,12,13,14,15]. A key element of this mini-review will be to present and analyze the preventative options, via vaccination, available to common respiratory tract diseases and how such treatment options are designed and delivered.
In particular, we will closely examine the option of intranasal (IN) delivery for respiratory tract illnesses. IN administration offers numerous advantages to the delivery of both therapeutics and prophylactics due to the obvious co-localization of the treatment proximal to infection.
Based upon current collaborative efforts of the authors, we will also more closely examine pneumococcal disease as an important respiratory tract illness, especially as it relates to the elderly population, defined as individuals > 65 years old, a group that will greatly expand in size over the next 25 years [16]. The unique features of pneumococcal disease, its relationships to other respiratory tract illnesses (particularly influenza), and the consideration that must be given to vaccine development will be highlighted. Included in this analysis will be the potential role which IN vaccine delivery might serve.
As such, we will intertwine the impact of respiratory tract diseases, some of the key elements of disease progression, and the application of IN delivery in the treatment of these diseases. We will also link the IN delivery approach to elements of particular respiratory tract illnesses (focusing on pneumococcal disease) and how this administration route can facilitate immune reactivity, or effective treatment more generally, towards the foundations of disease and disease progression.

2. Main Respiratory Illnesses and Their Treatment Methods

Respiratory tract infectious diseases have a long history of affecting the quality of human life. In this section, we introduce this disease category more broadly, highlighting high profile examples, their historical and recent impact, and treatment options available (Table 1).
In Table 1, well-recognized infectious diseases are highlighted, all of which have direct impact upon the respiratory tract. Some of these diseases are relatively common and mild (i.e., influenza and the common cold); however, certain viral strains over time have had significant global impact, especially as it relates to flu pandemics. Other diseases, like pneumococcal disease and tuberculosis, are caused by bacterial pathogens. There is also the potential interplay between various respiratory tract diseases, such as that between pneumococcal disease and influenza, which will be discussed in greater detail later.
Table 1 also presents common treatment options for the pulmonary diseases listed. Notably, each disease includes a vaccine option, even those that are bacterial in nature and might be readily treated by antibiotics. In the case of bacterial-derived tuberculosis, antibiotic effectiveness can be limited by the latent state of the bacteria and/or the morphology and chemical composition of the mycobacterium responsible for disease [23,24,25,26,27]. The disease progression profile for pneumococcal disease (namely, in vivo biofilm formation) also poses challenges for effective antibiotic treatment [28,29,30,31,32,33]. Finally, like most other bacterial infectious disease targets, the active agents responsible for tuberculosis, pertussis, and pneumococcal disease are prone to development of antibiotic resistance [34,35,36,37,38,39]. As a result, all of the respiratory tract diseases listed in Table 1 also feature vaccine treatment options, with each of these routinely used to address the given disease.

3. Intranasal Vaccine Delivery

Table 1 includes vaccines as a consistent treatment option for the range of respiratory tract diseases highlighted. In this section, we will now introduce intranasal delivery as a vaccine administration route. As the name indicates, intranasal delivery means a vaccine formulation, which is introduced in the body through the nose. In the context of treatment options for respiratory tract diseases, this approach is viewed with great promise.
First, when compared to more traditional forms of vaccine administration methods (subcutaneous or intramuscular injection), intranasal administration offers a simpler, less invasive option, potentially leading to more compliance and less medical complications (localized infection and/or pain) due to traditional methods that require needle-based skin puncture [40], though it is acknowledged that overall effectiveness will depend on the consistent degree of IN administration, which is subject to the methodology of delivery or the skill of personnel overseeing the administration. In addition, in the context of vaccine delivery for the aforementioned respiratory tract diseases, intranasal delivery offers the prospect of a localized, mucosal immune response proximal to the target infectious disease [40,41].
Table 2 covers the broad use of intranasal delivery methods applied to the infectious diseases introduced in Table 1 (with the majority of these studies reporting similar or better results compared to traditional methods of intramuscular and subcutaneous administration). Spacing the analysis over a 12-year window, the total number of IN vaccine studies completed over this time period were directed at influenza. Whooping cough (pertussis) has a very established vaccine treatment regimen, and this may decrease newer research efforts for IN delivery methods. Whereas, diseases like influenza, pneumococcal disease, and tuberculosis feature some combination of challenging disease features, whether that be seasonal strain variation (influenza), degree of strain coverage and disease progression (pneumococcal disease), or disease state (active vs. latent, in the case of tuberculosis). As such, the complexities associated with these disease types may have spurred more recent research activity more generally with the inclusion of IN vaccine delivery methods in particular. Finally, the dominance in attention due to COVID-19 research over the last year offers an explanation for the recent uptick in IN delivery research [42] (with a noticeable downtrend for studies focused on influenza in that same time period).
Table 3 more closely examines the types of IN methods that have been utilized over the last 10 years, the rationale behind the methodology, general frequency of use, and distribution of application across common respiratory tract diseases. The approaches highlighted include direct IN administration (the addition/inhalation of a dry powder or instillation within a solution applied directly to the nostrils) and the inclusion of both physical (aerosolization) and chemical (various formulations) methods designed to influence bodily absorption and immune response. Applications generally span the respiratory tract diseases introduced in Table 1 and Table 2 with a heightened degree of usage for influenza and pneumococcal disease.

4. Pneumococcal Disease and the Elderly

The following section will feature an extended examination of pneumococcal disease, due both to overlapping collaborative expertise on the part of the authors and its connection to the themes of this mini-review. Of note, pneumococcal disease, derived from Streptococcus pneumoniae, is particularly relevant due to its broad global impact, especially on the very young, elderly, and resource limited [54,55,56,57]; its unique means of disease progression spanning the upper respiratory tract to various downstream locations in the body (including and prominently the lungs) [33,58]; its potentially devastating overlap with dual infectious diseases, predominantly influenza [9,10,55,59,60,61]; and the opportunity to address this disease through unique means of vaccine design and delivery, including intranasal administration.
Pneumococcal disease has a disproportional impact upon the elderly, where individuals ≥ 65 years old account for the majority of hospitalizations and deaths following pneumococcal infection [62]. The number of elderly is projected to double in the coming decades, reaching 2 billion by 2050 [63]. This poses a serious health concern as the elderly are more susceptible to infections, particularly those caused by S. pneumoniae [54], which are encapsulated Gram-positive bacteria that include 100 serotypes based on the composition of the capsular polysaccharide [62,64]. Upon colonization of the upper respiratory tract, these bacteria typically reside asymptomatically in the nasopharynx of healthy individuals [62], occurring in 10–40% of adults and up to 80–100% in children [65]. In individuals with compromised immunity, such as the elderly, pneumococci can spread and cause pneumonia as well as invasive pneumococcal diseases, including meningitis, endocarditis, and bacteremia [54]. Disease manifestation is in part driven by bacterial serotypes, as bacteria with different capsular polysaccharides vary considerably in their ability to cause invasive disease [66]. Despite available vaccine and antibiotic treatments, S. pneumoniae remain the leading cause of bacterial community-acquired pneumonia in the elderly [67] and according to the CDC are responsible for 900,000 cases of pneumonia and 400,000 hospitalizations in the U.S. yearly [68]. In a recent Active Bacterial Core surveillance report [69], individuals above 50 accounted for 71% of all invasive pneumococcal diseases cases and 82% of associated deaths [70,71], resulting in an estimated cost of $2.5 billion annually due to hospitalizations [72,73]. Of further concern is the increase in pneumococcal antibiotic resistance (thus, limiting traditional antibiotic use), classified by the 2019 CDC Antibiotic Resistance Threat Report as Serious and resulting in over a million drug-resistant infections yearly [74]. Strikingly, the elderly are more at risk of acquiring drug-resistant infections [68]. The risk of pneumococcal pneumonia is further enhanced dramatically (100-fold) by influenza A virus (IAV) co-infection [60,75], resulting in seasonal increases in lethal infections, the majority of which (70–85%) are in elderly individuals [60]. Without intervention, projected increases in the aging population will double pneumococcal-related health impacts and treatment costs in the coming decades [72], necessitating novel strategies to combat this infectious threat.
Two vaccines consisting of capsular polysaccharides that cover the most common disease-causing S. pneumoniae serotypes are recommended for the elderly [76]. The pneumococcal polysaccharide vaccine (PPSV or Pneumovax) covers 23 serotypes and triggers T cell-independent antibody (Ab) production with 56–75% efficacy (in non-elderly groups). The pneumococcal conjugate vaccine (PCV or Prevnar-13) contains polysaccharides from 13 strains covalently linked to a non-pathogenic diphtheria toxoid protein (CRM197) that triggers a T cell-dependent antibody response [76]. PCV provides protection against 74–88% of invasive pneumococcal disease cases (in non-elderly groups). The introduction of PCV in children leads to eradication of bacterial nasal colonization or carriage, thereby, reducing transmission and indirectly leading to a decline in infections within adults for strains included in the vaccine.
However, there are several issues associated with the currently licensed vaccines that limit their efficacy (defined as prevention of infection by pneumococci) against pneumococcal infections overall and particularly in the elderly population. The first is serotype coverage and replacement [77,78]. The above vaccine methods focused upon inhibiting initial colonization have prompted increased infections caused by “replacement” strains not included in the current vaccines. This prospect has been made more daunting by the sizable number of serotypes (currently 100 identified thus far [64]) that must be accounted for to enable full vaccine coverage [79,80]. Moreover, novel disease-associated non-encapsulated pneumococcal strains that carry antibiotic resistance genes have recently emerged [81], and these are not covered by the available licensed vaccines. The second issue with current vaccines is a failure to account for changes in pneumococcal biology during disease progression. S. pneumoniae typically reside asymptomatically in the nasopharynx of healthy individuals [62], and it is hypothesized that S. pneumoniae establish an asymptomatic biofilm on the nasopharyngeal epithelium by attenuating the production of virulence factors and concomitant inflammation [32,82,83,84]. In humans, pneumococcal carriage is believed to be a prerequisite of invasive disease [85,86], which occurs when immunity is compromised, as is observed in the elderly. The transition from benign colonizer to lethal pulmonary or systemic pathogen also involves changes in bacterial transcript profiles and morphology [83,87,88,89]. This was highlighted in recent studies that showed that the set of genes expressed by pneumococci during colonization were distinct from those expressed during lung infection as well as during bacteremia, indicating that the bacteria adapt to their host in an infection site/organ-specific manner [83,87]. Importantly, sets of conserved genes were upregulated across the several strains tested, suggesting they could be potential vaccine targets that induce strain-independent protection [87,89]. Similarly, it is well-established that regulation of capsule expression is required for bacterial virulence [90]. Capsule expression is required for evasion of entrapment by mucus in the airways; however, downregulation of capsule allows for efficient bacterial binding to the pulmonary epithelium [91]. Upon bacterial localization into deeper tissues, including the lower airways and the bloodstream, capsule formation is again required to evade phagocytosis and clearance by immune cells [80,91]. These findings have important implication on vaccine design, and vaccines that encompass capsular polysaccharides along with other bacterial factors key for establishment of lung infection or invasive disease (e.g., bacteremia) would be ideal for eliciting full host protection against infection. Finally, the third issue with current vaccines is reduced efficacy during aging. PPSV has been traditionally recommended for the elderly while PCV is now recommended for the most vulnerable elderly with underlying conditions [79,92]. While protective against bacteremia, the efficacy of both vaccines is limited against pneumonia in the elderly: PPSV and Prevnar-13 showed only 33% [93] and 45% protection against pneumonia, respectively [94,95]. This age-driven decline in pneumococcal immunization and conjugate vaccine efficacy has been recapitulated in mice [96,97]. The moderate ability of current vaccines in protecting against pneumonia in the elderly necessitates better strategies to boost vaccine efficacy.
Immunosenescence, the overall dysregulation in immunity that occurs with age, drives the increased susceptibility of the elderly to invasive pneumococcal diseases and the linked decline in vaccine efficacy [98,99,100]. Several aspects of the age-related decline in adaptive immunity have been characterized [97,101,102]. Antibody production by B cells can depend on T cells such as that elicited by PCV [103] or be T cell-independent as elicited by PPSV [104]. Aging leads to defects in both T cell-dependent and -independent antibody production [105,106], limiting current vaccine efficacy [105,107]. Following vaccination with PPSV, both antibody levels and functionality, defined as the ability of antibodies to opsonize and enhance phagocytic uptake of bacteria (opsonophagocytic activity or OPA), were significantly impaired among the elderly when compared to younger individuals [108]. The drivers of declined vaccine response in aging are multi-factorial and may be attributed to chronic inflammation [105], intrinsic defects in B cells including reduced repertoire, defects in key transcription factors and reduction in AID, the enzyme required for class-switch recombination and somatic hypermutation, as well as overall defects in T cell signaling and proliferation [76,109] and in T-follicular helper cells that mediate antibody production by B cells [110,111]. Thus, vaccines that enhance antigen presentation and simultaneously target more than one arm of the immune response are attractive avenues to boost memory responses in the elderly.
In the U.S., influenza accounts for over 10,000 deaths annually and over 40,000 deaths during epidemic years [112]. Individuals ≥ 65 years account for a staggering 88% of all influenza-associated deaths [112]. A high percentage of deaths during major influenza pandemics are due to secondary bacterial pneumonia, particularly by S. pneumoniae [113]. In fact, the risk of invasive pneumococcal infection is enhanced 100-fold by influenza A virus (IAV) infection [112], resulting in the seasonal peak of invasive pneumococcal disease during influenza outbreaks [60]. The means by which IAV promotes bacterial infection are manifold and have been characterized using mouse models of co-infection [114]. As mentioned, S. pneumoniae typically colonizes asymptomatically, and it is thought that IAV infection triggers bacterial release from the nasopharynx into the lungs, priming the infection [115]. First, IAV exposure enhances the nutritional environment for pneumococcus in the nasopharynx by increasing the availability of sialylated substrates and increasing rates of pneumococcal carriage [116]. Second, factors such as ATP, released by viral infected host cells, promote the dispersion of pneumococci from nasopharynx biofilms to the lower respiratory tract [83,116,117]. The dispersed bacteria have altered transcriptional profiles and express increased levels of certain factors required for infection, thus, rendering them more virulent [83,89]. Third, IAV infection of the lung, through inflammation and oxidative stress, damages the pulmonary epithelium, facilitating pulmonary bacterial colonization and rendering the lung more permissive for subsequent replication. In addition, the adaptive immune response to IAV, mediated by type II and I IFNs produced by anti-viral T cells, impairs both the recruitment of innate immune cells and their ability to kill bacteria [118,119]. The combined tissue damage and compromised immune functions promote systemic spread of S. pneumoniae [118,120,121]. As IAV infection alters both the host immune response and bacterial virulence, updated vaccine formulations that maintain protection during co-infections are required.
Built specifically to address weaknesses in PPSV and PCV vaccine options, the liposomal encapsulation of polysaccharide (LEPS) vaccine platform (Figure 1) broadly protects against multiple stages of pneumococcal infection. The LEPS formulation features a liposomal vaccine carrier that encapsulates serotype-specific polysaccharides with the capability to scale to any desired number required for vaccine coverage, which is a technical and economic impossibility with current glycoconjugate formulations. The LEPS vehicle also includes a non-covalent attachment mechanism (via either metal-based chelation or biotin affinity) to affix surface proteins, including CRM197 or new protein antigens that have been identified within virulence progression steps for S. pneumoniae, such as proteins temporally displayed by invasive biofilm-dispersed bacteria following influenza co-infection [88,122]. Importantly, this binding mechanism mimics the immunological outcome of Prevnar-13 (i.e., IgM to IgG class switching); triggers Th2, Th1, and Th17 responses (which as indicated above are crucial for overall vaccine effectiveness); and extends recognition to >70 S. pneumoniae serotypes due to multiple antigen types (polysaccharide and protein) targeting multiple phases of pneumococcal disease progression (including those traditionally triggered by influenza co-infection) [88,122]. Each feature thus positions the LEPS vaccine as a new and improved option for pneumococcal disease.

5. Intranasal Vaccine Delivery for Pneumococcal Disease

One approach that could boost vaccine-mediated immunity against pulmonary infections is to elicit mucosal immune responses, which entails reactivity at the interface of the external environment and the mucus membranes of the respiratory system. This, of course, is a primary motivator for IN vaccine administration. In previous efforts with the LEPS vaccine platform applied towards pneumococcal disease, administration routes had utilized more common intramuscular and subcutaneous injections (with inclusion of the alum adjuvant) [88,122]. Once localized in these locations, the LEPS particles are likely recognized by probing phagocytes, engulfed, and processed for antigen presentation. The LEPS particles may also act in an adjuvant-like manner, activating immune cells, enhancing antigen uptake, and eliciting a more robust immune response.
However, other efforts in pneumococcal disease vaccine research have begun testing the potential for IN administration. In mice, intranasal immunizations with killed [123] or live pneumococci were shown to protect against invasive pneumococcal disease in young hosts [96,124,125,126]. This protection was mediated by both induction of systemic antibody responses [96] as well as mucosal cell-mediated responses including IL-17-producing lung-resident CD4+ T cells [124,125,126]. Importantly, in humans, experimental pneumococcal carriage, where live pneumococci are administered intranasally to volunteers, similarly elicited systemic antibody responses [127,128], elicited lung IL-17+ CD4+ memory T cells [129], stimulated tissue resident innate immune cells [130], and protected against re-colonization by the same serotype [131]. Further, intranasal delivery of pneumococcal protein-based vaccines along with adjuvants protected against invasive disease in mouse models [132]. Thus, intranasal immunizations that trigger systemic and mucosal immune responses are likely viable strategies to elicit host protection against lung infections. Intranasal immunization offers other advantages over traditional immunization administration methods, namely, the lack of injection-driven complications including infections at the administration site and a simple, non-invasive administration that could potentially be self-administered or not require expertise of registered nurses (a plus in remote regions in countries where accessibility is an issue).
There are currently only two licensed intranasal vaccines against influenza A and B viruses, FluMist/Fluenz® (MedImmune, Gaithersburg, MD, USA) and Nasovac® (Serum Institute of India Ltd. Hadapsar, India). Both vaccines consist of live-attenuated strains. Intranasal vaccines against a few other pathogens including SARS-CoV-2, Respiratory Syncytial Virus (RSV) and B. pertussis have also reached clinical trials ( However, the lack of safe mucosal adjuvants has been an obstacle to successful widespread intranasal vaccinations in humans [133,134]. No mucosal adjuvants have been approved for human use [135], and alum-based adjuvants, commonly used in more traditional vaccine administrations, have shown the potential for several deleterious effects (local tissue irritation, biased immune response) when administered intranasally [136,137]. However, intranasal delivery in the absence of adjuvants may not elicit protective immune responses and could alternatively induce tolerance [138].
Liposomes have shown potential as adjuvants, as have other formulations and additions (such as the inclusion of CpG oligodeoxynucleotide) [137,139,140,141,142,143,144]. As such, vaccine designs that leverage liposomal antigen delivery (such as the LEPS platform introduced above, for example) may very well support efforts in intranasal administration. In doing so, however, liposomal formulations must account for natural forms of bodily defense against intranasal entry of foreign particles, including mucociliary clearance and various barriers to cellular entry [145]. Many liposomal formulation may be prone to these challenges due to a negative surface charge that provides an electrostatic barrier to the interaction with negatively charged mucus and the antigen presenting cells located in the nasal cavity [146]; liposomal vaccine carriers may also lack in mechanical stability when delivered to the nasal passage.
Table 4 summarizes IN administration efforts in more detail for pneumococcal disease application. Here, these studies, all conducted over the last 10 years, show positive IN vaccine efforts for pneumococcal disease. Nearly all of those listed use a direct addition of the antigen content to the nasal region, with only a couple of entries using some sort of material-based formulation to assist in nasal localization and/or immune reactivity. The majority of cases rely upon subunit protein antigens, particularly those that have been identified as a promising marker of virulence. If included, adjuvant content spans non-biologic (liposomal, polymeric, alum) and biologic (chitosan, various bacterial toxins, macromolecules) materials. Though it should be noted that there have been previous concerns of host toxicity associated with bacterial-derived toxoid protein formulations when administered intranasally [133,134].

6. Conclusions

Respiratory tract diseases have a long history of affecting human health, with ongoing and recent events emphasizing this historical impact. The pathogens responsible for these diseases span bacterial and viral agents, and though antibiotics have been and continue to be used for the bacterial sources of disease, vaccines have emerged as dominant options for all the main diseases highlighted in this mini-review, spanning influenza, pneumococcal disease, pertussis, tuberculosis, and of course COVID-19. Given the localized disease impact to the pulmonary system, intranasal (IN) vaccine delivery offers a logical option to enhance the eventual immune response to the responsible infectious agents. Here, we have outlined IN utility, prevalence, and approaches for respiratory tract diseases, with an emphasis on vaccine administration for pneumococcal disease, which has a broad impact globally, especially amongst the elderly, and can be particularly synergistic with influenza co-infection. The advantages of IN vaccine delivery may offer new and better vaccine regimens for pneumococcal disease, and several more recent efforts towards this end highlight ongoing approaches that utilize a range of sub-unit and cellular antigenic cargo.

Author Contributions

W.W., J.B., and M.B. conducted the literature analyses and contributed to the writing of the manuscript. B.A.P. and E.N.B.G. designed content, contributed to writing, and oversaw editing of the manuscript. All authors have read and agreed to the published version of the manuscript.


This research was funded by the National Institutes of Health (NIA), grant number AG064215.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Liu, P.V. Medical Microbiology, 4th ed.; Baron, S., Ed.; University of Texas Medical Branch at Galveston: Galveston, TX, USA, 1996. [Google Scholar]
  2. Mizgerd, J.P. Respiratory infection and the impact of pulmonary immunity on lung health and disease. Am. J. Respir. Crit. Care Med. 2012, 186, 824–829. [Google Scholar] [CrossRef]
  3. Heikkinen, T.; Chonmaitree, T. Importance of respiratory viruses in acute otitis media. Clin. Microbiol. Rev. 2003, 16, 230–241. [Google Scholar] [CrossRef][Green Version]
  4. Morris, P.S. Upper respiratory tract infections (including otitis media). Pediatr. Clin. N. Am. 2009, 56, 101–117. [Google Scholar] [CrossRef]
  5. Carvajal, L.A.; Pérez, C.P. Epidemiology of Respiratory Infections. Pediatr. Respir. Dis. 2020, 263–272. [Google Scholar] [CrossRef][Green Version]
  6. Treanor, J.; Falsey, A. Respiratory viral infections in the elderly. Antivir. Res. 1999, 44, 79–102. [Google Scholar] [CrossRef]
  7. Meyer, K.C. Lung infections and aging. Ageing Res. Rev. 2004, 3, 55–67. [Google Scholar] [CrossRef]
  8. Abelenda-Alonso, G.; Rombauts, A.; Gudiol, C.; Meije, Y.; Ortega, L.; Clemente, M.; Ardanuy, C.; Niubo, J.; Carratala, J. Influenza and Bacterial Coinfection in Adults with Community-Acquired Pneumonia Admitted to Conventional Wards: Risk Factors, Clinical Features, and Outcomes. Open Forum Infect. Dis. 2020, 7, ofaa066. [Google Scholar] [CrossRef] [PubMed][Green Version]
  9. Zhou, H.; Haber, M.; Ray, S.; Farley, M.M.; Panozzo, C.A.; Klugman, K.P. Invasive pneumococcal pneumonia and respiratory virus co-infections. Emerg. Infect. Dis. 2012, 18, 294–297. [Google Scholar] [CrossRef] [PubMed]
  10. Wang, X.Y.; Kilgore, P.E.; Lim, K.A.; Wang, S.M.; Lee, J.; Deng, W.; Mo, M.Q.; Nyambat, B.; Ma, J.C.; Favorov, M.O.; et al. Influenza and bacterial pathogen coinfections in the 20th century. Interdiscip. Perspect. Infect. Dis. 2011, 2011, 146376. [Google Scholar] [CrossRef] [PubMed][Green Version]
  11. Zoorob, R.; Sidani, M.A.; Fremont, R.D.; Kihlberg, C. Antibiotic use in acute upper respiratory tract infections. Am. Fam. Physician 2012, 86, 817–822. [Google Scholar]
  12. Liberati, A.; D’Amico, R.; Pifferi, S.; Torri, V.; Brazzi, L.; Parmelli, E. Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care. Cochrane Database Syst. Rev. 2009, CD000022. [Google Scholar] [CrossRef][Green Version]
  13. Abed, Y.; Boivin, G. Treatment of respiratory virus infections. Antivir. Res. 2006, 70, 1–16. [Google Scholar] [CrossRef]
  14. Whitney, C.G.; Harper, S.A. Lower respiratory tract infections: Prevention using vaccines. Infect. Dis. Clin. N. Am. 2004, 18, 899–917. [Google Scholar] [CrossRef]
  15. Greenberg, H.B.; Piedra, P.A. Immunization against viral respiratory disease: A review. Pediatr. Infect. Dis. J. 2004, 23, S254–S261. [Google Scholar] [CrossRef] [PubMed]
  16. Ortman, J.M.; Velkoff, V.A. An Aging Nation: The Older Population in the United States; Current Population Reports. 2014. Available online: (accessed on 1 March 2021).
  17. Chow, E.J.; Doyle, J.D.; Uyeki, T.M. Influenza virus-related critical illness: Prevention, diagnosis, treatment. Crit. Care 2019, 23, 214. [Google Scholar] [CrossRef] [PubMed][Green Version]
  18. Torres, A.; Cilloniz, C.; Blasi, F.; Chalmers, J.D.; Gaillat, J.; Dartois, N.; Schmitt, H.J.; Welte, T. Burden of pneumococcal community-acquired pneumonia in adults across Europe: A literature review. Respir. Med. 2018, 137, 6–13. [Google Scholar] [CrossRef] [PubMed][Green Version]
  19. Machado, M.B.; Passos, S.D. Severe Pertussis in Childhood: Update and Controversy-Systematic Review. Rev. Paul. Pediatr. 2019, 37, 351–362. [Google Scholar] [CrossRef]
  20. Suarez, I.; Funger, S.M.; Kroger, S.; Rademacher, J.; Fatkenheuer, G.; Rybniker, J. The Diagnosis and Treatment of Tuberculosis. Dtsch. Arztebl. Int. 2019, 116, 729–735. [Google Scholar] [CrossRef] [PubMed]
  21. Stasi, C.; Fallani, S.; Voller, F.; Silvestri, C. Treatment for COVID-19: An overview. Eur. J. Pharmacol. 2020, 889, 173644. [Google Scholar] [CrossRef]
  22. Liu, J.; Xie, W.; Wang, Y.; Xiong, Y.; Chen, S.; Han, J.; Wu, Q. A comparative overview of COVID-19, MERS and SARS: Review article. Int. J. Surg. 2020, 81, 1–8. [Google Scholar] [CrossRef]
  23. Smith, T.; Wolff, K.A.; Nguyen, L. Molecular biology of drug resistance in Mycobacterium tuberculosis. Curr. Top. Microbiol. Immunol. 2013, 374, 53–80. [Google Scholar] [CrossRef][Green Version]
  24. Bellerose, M.M.; Proulx, M.K.; Smith, C.M.; Baker, R.E.; Ioerger, T.R.; Sassetti, C.M. Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis. mSystems 2020, 5. [Google Scholar] [CrossRef] [PubMed]
  25. Gideon, H.P.; Flynn, J.L. Latent tuberculosis: What the host “sees”? Immunol. Res. 2011, 50, 202–212. [Google Scholar] [CrossRef] [PubMed][Green Version]
  26. Kulka, K.; Hatfull, G.; Ojha, A.K. Growth of Mycobacterium tuberculosis biofilms. J. Vis. Exp. 2012. [Google Scholar] [CrossRef] [PubMed][Green Version]
  27. Manjelievskaia, J.; Erck, D.; Piracha, S.; Schrager, L. Drug-resistant TB: Deadly, costly and in need of a vaccine. Trans. R. Soc. Trop. Med. Hyg. 2016, 110, 186–191. [Google Scholar] [CrossRef][Green Version]
  28. Barkai, G.; Greenberg, D.; Givon-Lavi, N.; Dreifuss, E.; Vardy, D.; Dagan, R. Community prescribing and resistant Streptococcus pneumoniae. Emerg. Infect. Dis. 2005, 11, 829–837. [Google Scholar] [CrossRef]
  29. Butler, J.C.; Cetron, M.S. Pneumococcal drug resistance: The new “special enemy of old age”. Clin. Infect. Dis. 1999, 28, 730–735. [Google Scholar] [CrossRef][Green Version]
  30. Dagan, R.; Leibovitz, E.; Greenberg, D.; Yagupsky, P.; Fliss, D.M.; Leiberman, A. Dynamics of pneumococcal nasopharyngeal colonization during the first days of antibiotic treatment in pediatric patients. Pediatr. Infect. Dis. J. 1998, 17, 880–885. [Google Scholar] [CrossRef]
  31. Pichichero, M.E.; Casey, J.R. Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children. JAMA 2007, 298, 1772–1778. [Google Scholar] [CrossRef][Green Version]
  32. Marks, L.R.; Parameswaran, G.I.; Hakansson, A.P. Pneumococcal interactions with epithelial cells are crucial for optimal biofilm formation and colonization in vitro and in vivo. Infect. Immun. 2012, 80, 2744–2760. [Google Scholar] [CrossRef][Green Version]
  33. Loughran, A.J.; Orihuela, C.J.; Tuomanen, E.I. Streptococcus pneumoniae: Invasion and Inflammation. Microbiol. Spectr. 2019, 7. [Google Scholar] [CrossRef]
  34. Chen, H.H.; Stringer, A.; Eguale, T.; Rao, G.G.; Ozawa, S. Impact of Antibiotic Resistance on Treatment of Pneumococcal Disease in Ethiopia: An Agent-Based Modeling Simulation. Am. J. Trop. Med. Hyg. 2019, 101, 1042–1053. [Google Scholar] [CrossRef]
  35. Kim, L.; McGee, L.; Tomczyk, S.; Beall, B. Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: A United States Perspective. Clin. Microbiol. Rev. 2016, 29, 525–552. [Google Scholar] [CrossRef] [PubMed][Green Version]
  36. Mabhula, A.; Singh, V. Drug-resistance in Mycobacterium tuberculosis: Where we stand. Medchemcomm 2019, 10, 1342–1360. [Google Scholar] [CrossRef] [PubMed]
  37. Yang, Y.; Yao, K.; Ma, X.; Shi, W.; Yuan, L.; Yang, Y. Variation in Bordetella pertussis Susceptibility to Erythromycin and Virulence-Related Genotype Changes in China (1970–2014). PLoS ONE 2015, 10, e0138941. [Google Scholar] [CrossRef] [PubMed][Green Version]
  38. Xu, Z.; Wang, Z.; Luan, Y.; Li, Y.; Liu, X.; Peng, X.; Octavia, S.; Payne, M.; Lan, R. Genomic epidemiology of erythromycin-resistant Bordetella pertussis in China. Emerg. Microbes Infect. 2019, 8, 461–470. [Google Scholar] [CrossRef] [PubMed][Green Version]
  39. Kamachi, K.; Duong, H.T.; Dang, A.D.; Hai, T.; Do, D.; Koide, K.; Otsuka, N.; Shibayama, K.; Hoang, H.T.T. Macrolide-Resistant Bordetella pertussis, Vietnam, 2016–2017. Emerg. Infect. Dis. 2020, 26, 2511–2513. [Google Scholar] [CrossRef] [PubMed]
  40. Yusuf, H.; Kett, V. Current prospects and future challenges for nasal vaccine delivery. Hum. Vaccines Immunother. 2017, 13, 34–45. [Google Scholar] [CrossRef]
  41. Ogra, P.L.; Faden, H.; Welliver, R.C. Vaccination strategies for mucosal immune responses. Clin. Microbiol. Rev. 2001, 14, 430–445. [Google Scholar] [CrossRef][Green Version]
  42. Wang, J.; Peng, Y.; Xu, H.; Cui, Z.; Williams, R.O. The COVID-19 Vaccine Race: Challenges and Opportunities in Vaccine Formulation. AAPS PharmSciTech 2020, 21, 225. [Google Scholar] [CrossRef]
  43. Tomar, J.; Patil, H.P.; Bracho, G.; Tonnis, W.F.; Frijlink, H.W.; Petrovsky, N.; Vanbever, R.; Huckriede, A.; Hinrichs, W.L.J. Advax augments B and T cell responses upon influenza vaccination via the respiratory tract and enables complete protection of mice against lethal influenza virus challenge. J. Control. Release 2018, 288, 199–211. [Google Scholar] [CrossRef]
  44. Dehghan, S.; Tafaghodi, M.; Bolourieh, T.; Mazaheri, V.; Torabi, A.; Abnous, K.; Tavassoti Kheiri, M. Rabbit nasal immunization against influenza by dry-powder form of chitosan nanospheres encapsulated with influenza whole virus and adjuvants. Int. J. Pharm. 2014, 475, 1–8. [Google Scholar] [CrossRef]
  45. Li, H.S.; Shin, M.K.; Singh, B.; Maharjan, S.; Park, T.E.; Kang, S.K.; Yoo, H.S.; Hong, Z.S.; Cho, C.S.; Choi, Y.J. Nasal immunization with mannan-decorated mucoadhesive HPMCP microspheres containing ApxIIA toxin induces protective immunity against challenge infection with Actinobacillus pleuropneumoiae in mice. J. Control. Release 2016, 233, 114–125. [Google Scholar] [CrossRef]
  46. Wu, M.; Zhao, H.; Li, M.; Yue, Y.; Xiong, S.; Xu, W. Intranasal Vaccination with Mannosylated Chitosan Formulated DNA Vaccine Enables Robust IgA and Cellular Response Induction in the Lungs of Mice and Improves Protection against Pulmonary Mycobacterial Challenge. Front. Cell. Infect. Microbiol. 2017, 7, 445. [Google Scholar] [CrossRef]
  47. Reljic, R.; Sibley, L.; Huang, J.M.; Pepponi, I.; Hoppe, A.; Hong, H.A.; Cutting, S.M. Mucosal vaccination against tuberculosis using inert bioparticles. Infect. Immun. 2013, 81, 4071–4080. [Google Scholar] [CrossRef] [PubMed][Green Version]
  48. Khademi, F.; Derakhshan, M.; Yousefi-Avarvand, A.; Najafi, A.; Tafaghodi, M. A novel antigen of Mycobacterium tuberculosis and MPLA adjuvant co-entrapped into PLGA: DDA hybrid nanoparticles stimulates mucosal and systemic immunity. Microb. Pathog. 2018, 125, 507–513. [Google Scholar] [CrossRef]
  49. Wang, D.; Lu, J.; Yu, J.; Hou, H.; Leenhouts, K.; Van Roosmalen, M.L.; Gu, T.; Jiang, C.; Kong, W.; Wu, Y. A Novel PspA Protein Vaccine Intranasal Delivered by Bacterium-Like Particles Provides Broad Protection against Pneumococcal Pneumonia in Mice. Immunol. Investig. 2018, 47, 403–415. [Google Scholar] [CrossRef]
  50. Shim, B.S.; Choi, Y.K.; Yun, C.H.; Lee, E.G.; Jeon, Y.S.; Park, S.M.; Cheon, I.S.; Joo, D.H.; Cho, C.H.; Song, M.S.; et al. Sublingual immunization with M2-based vaccine induces broad protective immunity against influenza. PLoS ONE 2011, 6, e27953. [Google Scholar] [CrossRef][Green Version]
  51. Liu, H.; Patil, H.P.; de Vries-Idema, J.; Wilschut, J.; Huckriede, A. Evaluation of mucosal and systemic immune responses elicited by GPI-0100- adjuvanted influenza vaccine delivered by different immunization strategies. PLoS ONE 2013, 8, e69649. [Google Scholar] [CrossRef] [PubMed][Green Version]
  52. Roy, C.J.; Ault, A.; Sivasubramani, S.K.; Gorres, J.P.; Wei, C.J.; Andersen, H.; Gall, J.; Roederer, M.; Rao, S.S. Aerosolized adenovirus-vectored vaccine as an alternative vaccine delivery method. Respir. Res. 2011, 12, 153. [Google Scholar] [CrossRef][Green Version]
  53. Kong, I.G.; Sato, A.; Yuki, Y.; Nochi, T.; Takahashi, H.; Sawada, S.; Mejima, M.; Kurokawa, S.; Okada, K.; Sato, S.; et al. Nanogel-based PspA intranasal vaccine prevents invasive disease and nasal colonization by Streptococcus pneumoniae. Infect. Immun. 2013, 81, 1625–1634. [Google Scholar] [CrossRef][Green Version]
  54. Chong, C.P.; Street, P.R. Pneumonia in the elderly: A review of the epidemiology, pathogenesis, microbiology, and clinical features. South. Med. J. 2008, 101, 1141–1145, quiz 1132, 1179. [Google Scholar] [CrossRef]
  55. Wunderink, R.G.; Waterer, G. Advances in the causes and management of community acquired pneumonia in adults. BMJ 2017, 358, j2471. [Google Scholar] [CrossRef]
  56. Stupka, J.E.; Mortensen, E.M.; Anzueto, A.; Restrepo, M.I. Community-acquired pneumonia in elderly patients. Aging Health 2009, 5, 763–774. [Google Scholar] [CrossRef] [PubMed][Green Version]
  57. Shiri, T.; Khan, K.; Keaney, K.; Mukherjee, G.; McCarthy, N.D.; Petrou, S. Pneumococcal Disease: A Systematic Review of Health Utilities, Resource Use, Costs, and Economic Evaluations of Interventions. Value Health 2019, 22, 1329–1344. [Google Scholar] [CrossRef]
  58. de Sevilla, M.F.; Garcia-Garcia, J.J.; Esteva, C.; Moraga, F.; Hernandez, S.; Selva, L.; Coll, F.; Ciruela, P.; Planes, A.M.; Codina, G.; et al. Clinical presentation of invasive pneumococcal disease in Spain in the era of heptavalent conjugate vaccine. Pediatr. Infect. Dis. J. 2012, 31, 124–128. [Google Scholar] [CrossRef] [PubMed]
  59. Short, K.R.; Habets, M.N.; Hermans, P.W.; Diavatopoulos, D.A. Interactions between Streptococcus pneumoniae and influenza virus: A mutually beneficial relationship? Future Microbiol. 2012, 7, 609–624. [Google Scholar] [CrossRef] [PubMed]
  60. Shrestha, S.; Foxman, B.; Weinberger, D.M.; Steiner, C.; Viboud, C.; Rohani, P. Identifying the interaction between influenza and pneumococcal pneumonia using incidence data. Sci. Transl. Med. 2013, 5, 191ra84. [Google Scholar] [CrossRef] [PubMed][Green Version]
  61. Nguyen, D.T.; Louwen, R.; Elberse, K.; van Amerongen, G.; Yuksel, S.; Luijendijk, A.; Osterhaus, A.D.; Duprex, W.P.; de Swart, R.L. Streptococcus pneumoniae Enhances Human Respiratory Syncytial Virus Infection In Vitro and In Vivo. PLoS ONE 2015, 10, e0127098. [Google Scholar] [CrossRef][Green Version]
  62. Kadioglu, A.; Weiser, J.N.; Paton, J.C.; Andrew, P.W. The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease. Nat. Rev. Microbiol. 2008, 6, 288–301. [Google Scholar] [CrossRef]
  63. Boe, D.M.; Boule, L.A.; Kovacs, E.J. Innate immune responses in the ageing lung. Clin. Exp. Immunol. 2017, 187, 16–25. [Google Scholar] [CrossRef] [PubMed][Green Version]
  64. Ganaie, F.; Saad, J.S.; McGee, L.; van Tonder, A.J.; Bentley, S.D.; Lo, S.W.; Gladstone, R.A.; Turner, P.; Keenan, J.D.; Breiman, R.F.; et al. A New Pneumococcal Capsule Type, 10D, is the 100th Serotype and Has a Large cps Fragment from an Oral Streptococcus. mBio 2020, 11. [Google Scholar] [CrossRef] [PubMed]
  65. Obaro, S.; Adegbola, R. The pneumococcus: Carriage, disease and conjugate vaccines. J. Med. Microbiol. 2002, 51, 98–104. [Google Scholar] [CrossRef] [PubMed][Green Version]
  66. Weiser, J.N.; Ferreira, D.M.; Paton, J.C. Streptococcus pneumoniae: Transmission, colonization and invasion. Nat. Rev. Microbiol. 2018, 16, 355–367. [Google Scholar] [CrossRef]
  67. Henig, O.; Kaye, K.S. Bacterial Pneumonia in Older Adults. Infect. Dis. Clin. N. Am. 2017, 31, 689–713. [Google Scholar] [CrossRef]
  68. Centers for Disease Control and Prevention. Available online: (accessed on 1 March 2021).
  69. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance Report, Emerging Infections Program. Network, Streptococcus Pneumoniae. 2017. Available online: (accessed on 1 March 2021).
  70. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance Report EIPN, Group A Streptococcus—2015, Findings/Survreports/Gas15.pdf Avtihwcgar-2015. 2015. Available online: (accessed on 1 March 2021).
  71. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance Report EIPN, Streptococcus Pneumoniae. 2016. Available online: (accessed on 1 March 2021).
  72. Wroe, P.C.; Finkelstein, J.A.; Ray, G.T.; Linder, J.A.; Johnson, K.M.; Rifas-Shiman, S.; Moore, M.R.; Huang, S.S. Aging population and future burden of pneumococcal pneumonia in the United States. J. Infect. Dis. 2012, 205, 1589–1592. [Google Scholar] [CrossRef]
  73. Drijkoningen, J.J.; Rohde, G.G. Pneumococcal infection in adults: Burden of disease. Clin. Microbiol. Infect. 2014, 20 (Suppl. 5), 45–51. [Google Scholar] [CrossRef][Green Version]
  74. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance Report EIPN, S.p. 2019. Available online: (accessed on 1 March 2021).
  75. Thompson, M.G.; Shay, D.K.; Zhou, H.; Bridges, C.B.; Cheng, P.Y.; Burns, E.; Bresee, J.S.; Cox, N.J. Estimates of Deaths Associated with Seasonal Influenza-United States, 1976–2007. JAMA J. Am. Med Assoc. 2010, 304, 1778–1780, reprinted in MMWR 2010, 59, 1057–1062. [Google Scholar]
  76. Chen, W.H.; Kozlovsky, B.F.; Effros, R.B.; Grubeck-Loebenstein, B.; Edelman, R.; Sztein, M.B. Vaccination in the elderly: An immunological perspective. Trends Immunol. 2009, 30, 351–359. [Google Scholar] [CrossRef][Green Version]
  77. Hanage, W.P. Serotype-specific problems associated with pneumococcal conjugate vaccination. Future Microbiol. 2008, 3, 23–30. [Google Scholar] [CrossRef]
  78. Berical, A.C.; Harris, D.; Dela Cruz, C.S.; Possick, J.D. Pneumococcal Vaccination Strategies. An Update and Perspective. Ann. Am. Thorac. Soc. 2016, 13, 933–944. [Google Scholar] [CrossRef][Green Version]
  79. Musher, D. Pneumococcal Vaccination in Adults; Bartlett, J.G., Ed.; Wolters Kluwer: Alphen aan den Rijn, The Netherlands, 2017. [Google Scholar]
  80. Luck, J.N.; Tettelin, H.; Orihuela, C.J. Sugar-Coated Killer: Serotype 3 Pneumococcal Disease. Front. Cell. Infect. Microbiol. 2020, 10. [Google Scholar] [CrossRef] [PubMed]
  81. Keller, L.E.; Robinson, D.A.; McDaniel, L.S. Nonencapsulated Streptococcus pneumoniae: Emergence and Pathogenesis. mBio 2016, 7, e01792. [Google Scholar] [CrossRef][Green Version]
  82. Chao, Y.; Marks, L.R.; Pettigrew, M.M.; Hakansson, A.P. Streptococcus pneumoniae biofilm formation and dispersion during colonization and disease. Front. Cell. Infect. Microbiol. 2014, 4, 194. [Google Scholar] [CrossRef][Green Version]
  83. Marks, L.R.; Davidson, B.A.; Knight, P.R.; Hakansson, A.P. Interkingdom signaling induces Streptococcus pneumoniae biofilm dispersion and transition from asymptomatic colonization to disease. mBio 2013, 4. [Google Scholar] [CrossRef][Green Version]
  84. Blanchette-Cain, K.; Hinojosa, C.A.; Babu, R.A.S.; Lizcano, A.; Gonzalez-Juarbe, N.; Munoz-Almagro, C.; Sanchez, C.J.; Bergman, M.A.; Orihuela, C.J. Streptococcus pneumoniae Biofilm Formation Is Strain Dependent, Multifactorial, and Associated with Reduced Invasiveness and Immunoreactivity during Colonization. mBio 2013, 4. [Google Scholar] [CrossRef] [PubMed][Green Version]
  85. Bogaert, D.; de Groot, R.; Hermans, P.W.M. Streptococcus pneumoniae colonisation: The key to pneumococcal disease. Lancet Infect. Dis. 2004, 4, 144–154. [Google Scholar] [CrossRef]
  86. Simell, B.; Auranen, K.; Kayhty, H.; Goldblatt, D.; Dagan, R.; O’Brien, K.L.; Grp, P.C. The fundamental link between pneumococcal carriage and disease. Expert Rev. Vaccines 2012, 11, 841–855. [Google Scholar] [CrossRef] [PubMed][Green Version]
  87. D’Mello, A.; Riegler, A.N.; Martinez, E.; Beno, S.M.; Ricketts, T.D.; Foxman, E.F.; Orihuela, C.J.; Tettelin, H. An in vivo atlas of host-pathogen transcriptomes during Streptococcus pneumoniae colonization and disease. Proc. Natl. Acad. Sci. USA 2020, 117, 33507–33518. [Google Scholar] [CrossRef] [PubMed]
  88. Jones, C.H.; Zhang, G.; Nayerhoda, R.; Beitelshees, M.; Hill, A.; Rostami, P.; Li, Y.; Davidson, B.A.; Knight, P., 3rd; Pfeifer, B.A. Comprehensive vaccine design for commensal disease progression. Sci. Adv. 2017, 3, e1701797. [Google Scholar] [CrossRef][Green Version]
  89. Pettigrew, M.M.; Marks, L.R.; Kong, Y.; Gent, J.F.; Roche-Hakansson, H.; Hakansson, A.P. Streptococcus pneumoniae and influenza: Dynamic changes in the pneumococcal transcriptome during transition from biofilm formation to invasive disease. Infect. Immun. 2014. [Google Scholar] [CrossRef] [PubMed][Green Version]
  90. Shainheit, M.G.; Muie, M.; Camilli, A. The Core Promoter of the Capsule Operon of Streptococcus pneumoniae Is Necessary for Colonization and Invasive Disease. Infect. Immun. 2014, 82, 694–705. [Google Scholar] [CrossRef][Green Version]
  91. Dockrell, D.H.; Whyte, M.K.B.; Mitchell, T.J. Pneumococcal pneumonia: Mechanisms of infection and resolution. Chest 2012, 142, 482–491. [Google Scholar] [CrossRef] [PubMed][Green Version]
  92. Matanock, A.L.G.; Gierke, R.; Kobayashi, M.; Leidner, A.; Pilishvili, T. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged ≥65 Years: Updated Recommendations of the Advisory Committee on Immunization Practices. 2019; pp. 1069–1075. Available online: (accessed on 1 March 2021).
  93. Suzuki, M.; Dhoubhadel, B.G.; Ishifuji, T.; Yasunami, M.; Yaegashi, M.; Asoh, N.; Ishida, M.; Hamaguchi, S.; Aoshima, M.; Ariyoshi, K.; et al. Serotype-specific effectiveness of 23-valent pneumococcal polysaccharide vaccine against pneumococcal pneumonia in adults aged 65 years or older: A multicentre, prospective, test-negative design study. Lancet Infect. Dis. 2017, 17, 313–321. [Google Scholar] [CrossRef]
  94. Bonten, M.J.; Huijts, S.M.; Bolkenbaas, M.; Webber, C.; Patterson, S.; Gault, S.; van Werkhoven, C.H.; van Deursen, A.M.; Sanders, E.A.; Verheij, T.J.; et al. Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. N. Engl. J. Med. 2015, 372, 1114–1125. [Google Scholar] [CrossRef][Green Version]
  95. van Werkhoven, C.H.; Huijts, S.M.; Bolkenbaas, M.; Grobbee, D.E.; Bonten, M.J. The Impact of Age on the Efficacy of 13-valent Pneumococcal Conjugate Vaccine in Elderly. Clin. Infect. Dis. 2015, 61, 1835–1838. [Google Scholar] [CrossRef][Green Version]
  96. Bou Ghanem, E.N.; Maung, N.H.T.; Siwapornchai, N.; Goodwin, A.E.; Clark, S.; Munoz-Elias, E.J.; Camilli, A.; Gerstein, R.M.; Leong, J.M. Nasopharyngeal Exposure to Streptococcus pneumoniae Induces Extended Age-Dependent Protection against Pulmonary Infection Mediated by Antibodies and CD138(+) Cells. J. Immunol. 2018, 200, 3739–3751. [Google Scholar] [CrossRef]
  97. Sen, G.; Chen, Q.; Snapper, C.M. Immunization of aged mice with a pneumococcal conjugate vaccine combined with an unmethylated CpG-containing oligodeoxynucleotide restores defective immunoglobulin G antipolysaccharide responses and specific CD4+-T-cell priming to young adult levels. Infect. Immun. 2006, 74, 2177–2186. [Google Scholar] [CrossRef][Green Version]
  98. Krone, C.L.; van de Groep, K.; Trzcinski, K.; Sanders, E.A.; Bogaert, D. Immunosenescence and pneumococcal disease: An imbalance in host-pathogen interactions. Lancet Respir. Med. 2014, 2, 141–153. [Google Scholar] [CrossRef]
  99. Bhalla, M.; Simmons, S.R.; Abamonte, A.; Herring, S.E.; Roggensack, S.E.; Bou Ghanem, E.N. Extracellular adenosine signaling reverses the age-driven decline in the ability of neutrophils to kill Streptococcus pneumoniae. Aging Cell 2020, 19, e13218. [Google Scholar] [CrossRef] [PubMed]
  100. Simmons, S.R.; Bhalla, M.; Herring, S.E.; Tchalla, E.Y.I.; Bou Ghanem, E.N. Older but Not Wiser: The Age-Driven Changes in Neutrophil Responses during Pulmonary Infections. Infect. Immun. 2021, 89. [Google Scholar] [CrossRef]
  101. Meyer, K.C. The role of immunity in susceptibility to respiratory infection in the aging lung. Respir. Physiol. 2001, 128, 23–31. [Google Scholar] [CrossRef]
  102. Park, S.; Nahm, M.H. Older adults have a low capacity to opsonize pneumococci due to low IgM antibody response to pneumococcal vaccinations. Infect. Immun. 2011, 79, 314–320. [Google Scholar] [CrossRef] [PubMed][Green Version]
  103. Cerutti, A.; Puga, I.; Magri, G. The B cell helper side of neutrophils. J. Leukoc. Biol. 2013, 94, 677–682. [Google Scholar] [CrossRef] [PubMed][Green Version]
  104. Adderson, E.E. Antibody repertoires in infants and adults: Effects of T-independent and T-dependent immunizations. Springer Semin. Immunopathol. 2001, 23, 387–403. [Google Scholar] [CrossRef] [PubMed]
  105. Ridda, I.; Macintyre, C.R.; Lindley, R.; Gao, Z.; Sullivan, J.S.; Yuan, F.F.; McIntyre, P.B. Immunological responses to pneumococcal vaccine in frail older people. Vaccine 2009, 27, 1628–1636. [Google Scholar] [CrossRef]
  106. Buffa, S.; Bulati, M.; Pellicano, M.; Dunn-Walters, D.K.; Wu, Y.C.; Candore, G.; Vitello, S.; Caruso, C.; Colonna-Romano, G. B cell immunosenescence: Different features of naive and memory B cells in elderly. Biogerontology 2011, 12, 473–483. [Google Scholar] [CrossRef][Green Version]
  107. Bou Ghanem, E.N.; Clark, S.; Du, X.; Wu, D.; Camilli, A.; Leong, J.M.; Meydani, S.N. The alpha-tocopherol form of vitamin E reverses age-associated susceptibility to streptococcus pneumoniae lung infection by modulating pulmonary neutrophil recruitment. J. Immunol. 2015, 194, 1090–1099. [Google Scholar] [CrossRef][Green Version]
  108. Simell, B.; Vuorela, A.; Ekstrom, N.; Palmu, A.; Reunanen, A.; Meri, S.; Kayhty, H.; Vakevainen, M. Aging reduces the functionality of anti-pneumococcal antibodies and the killing of Streptococcus pneumoniae by neutrophil phagocytosis. Vaccine 2011, 29, 1929–1934. [Google Scholar] [CrossRef]
  109. Pinti, M.; Appay, V.; Campisi, J.; Frasca, D.; Fulop, T.; Sauce, D.; Larbi, A.; Weinberger, B.; Cossarizza, A. Aging of the immune system: Focus on inflammation and vaccination. Eur. J. Immunol. 2016, 46, 2286–2301. [Google Scholar] [CrossRef]
  110. Vinuesa, C.G.; Linterman, M.A.; Yu, D.; MacLennan, I.C. Follicular Helper T Cells. Annu. Rev. Immunol. 2016, 34, 335–368. [Google Scholar] [CrossRef]
  111. Gustafson, C.E.; Weyand, C.M.; Goronzy, J.J. T follicular helper cell development and functionality in immune ageing. Clin. Sci. 2018, 132, 1925–1935. [Google Scholar] [CrossRef] [PubMed]
  112. Centers for Disease Control and Prevention. Estimates of deaths associated with seasonal influenza—United States, 1976–2007. MMWR Morb. Mortal. Wkly. Rep. 2010, 59, 1057–1062. [Google Scholar]
  113. McCullers, J.A. Insights into the interaction between influenza virus and pneumococcus. Clin. Microbiol. Rev. 2006, 19, 571–582. [Google Scholar] [CrossRef] [PubMed][Green Version]
  114. Bakaletz, L.O. Viral-bacterial co-infections in the respiratory tract. Curr. Opin. Microbiol. 2017, 35, 30–35. [Google Scholar] [CrossRef]
  115. Davis, B.M.; Aiello, A.E.; Dawid, S.; Rohani, P.; Shrestha, S.; Foxman, B. Influenza and community-acquired pneumonia interactions: The impact of order and time of infection on population patterns. Am. J. Epidemiol. 2012, 175, 363–367. [Google Scholar] [CrossRef]
  116. Siegel, S.J.; Roche, A.M.; Weiser, J.N. Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source. Cell Host Microbe 2014, 16, 55–67. [Google Scholar] [CrossRef][Green Version]
  117. Diavatopoulos, D.A.; Short, K.R.; Price, J.T.; Wilksch, J.J.; Brown, L.E.; Briles, D.E.; Strugnell, R.A.; Wijburg, O.L. Influenza A virus facilitates Streptococcus pneumoniae transmission and disease. FASEB J. 2010, 24, 1789–1798. [Google Scholar] [CrossRef]
  118. Ballinger, M.N.; Standiford, T.J. Postinfluenza bacterial pneumonia: Host defenses gone awry. J. Interferon Cytokine Res. 2010, 30, 643–652. [Google Scholar] [CrossRef][Green Version]
  119. Metzger, D.W.; Sun, K. Immune dysfunction and bacterial coinfections following influenza. J. Immunol. 2013, 191, 2047–2052. [Google Scholar] [CrossRef][Green Version]
  120. McCullers, J.A. The co-pathogenesis of influenza viruses with bacteria in the lung. Nat. Rev. Microbiol. 2014, 12, 252–262. [Google Scholar] [CrossRef] [PubMed]
  121. Smith, A.M.; McCullers, J.A. Secondary bacterial infections in influenza virus infection pathogenesis. Curr. Top. Microbiol. Immunol. 2014, 385, 327–356. [Google Scholar] [CrossRef] [PubMed]
  122. Hill, A.B.; Beitelshees, M.; Nayerhoda, R.; Pfeifer, B.A.; Jones, C.H. Engineering a Next-Generation Glycoconjugate-Like Streptococcus pneumoniae Vaccine. ACS Infect. Dis. 2018, 4, 1553–1563. [Google Scholar] [CrossRef] [PubMed]
  123. Malley, R.; Lipsitch, M.; Stack, A.; Saladino, R.; Fleisher, G.; Pelton, S.; Thompson, C.; Briles, D.; Anderson, P. Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci. Infect. Immun. 2001, 69, 4870–4873. [Google Scholar] [CrossRef] [PubMed][Green Version]
  124. Smith, N.M.; Wasserman, G.A.; Coleman, F.T.; Hilliard, K.L.; Yamamoto, K.; Lipsitz, E.; Malley, R.; Dooms, H.; Jones, M.R.; Quinton, L.J.; et al. Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia. Mucosal. Immunol. 2018, 11, 220–235. [Google Scholar] [CrossRef] [PubMed]
  125. Shenoy, A.T.; Wasserman, G.A.; Arafa, E.I.; Wooten, A.K.; Smith, N.M.S.; Martin, I.M.C.; Jones, M.R.; Quinton, L.J.; Mizgerd, J.P. Lung CD4(+) resident memory T cells remodel epithelial responses to accelerate neutrophil recruitment during pneumonia. Mucosal Immunol. 2020, 13, 334–343. [Google Scholar] [CrossRef]
  126. Malley, R.; Trzcinski, K.; Srivastava, A.; Thompson, C.M.; Anderson, P.W.; Lipsitch, M. CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proc. Natl. Acad. Sci. USA 2005, 102, 4848–4853. [Google Scholar] [CrossRef][Green Version]
  127. Jochems, S.P.; de Ruiter, K.; Solorzano, C.; Voskamp, A.; Mitsi, E.; Nikolaou, E.; Carniel, B.F.; Pojar, S.; German, E.L.; Reine, J.; et al. Innate and adaptive nasal mucosal immune responses following experimental human pneumococcal colonization. J. Clin. Investig. 2019, 129, 4523–4538. [Google Scholar] [CrossRef][Green Version]
  128. Wright, A.K.; Ferreira, D.M.; Gritzfeld, J.F.; Wright, A.D.; Armitage, K.; Jambo, K.C.; Bate, E.; El Batrawy, S.; Collins, A.; Gordon, S.B. Human nasal challenge with Streptococcus pneumoniae is immunising in the absence of carriage. PLoS Pathog. 2012, 8, e1002622. [Google Scholar] [CrossRef]
  129. Wright, A.K.; Bangert, M.; Gritzfeld, J.F.; Ferreira, D.M.; Jambo, K.C.; Wright, A.D.; Collins, A.M.; Gordon, S.B. Experimental human pneumococcal carriage augments IL-17A-dependent T-cell defence of the lung. PLoS Pathog. 2013, 9, e1003274. [Google Scholar] [CrossRef]
  130. Mitsi, E.; Carniel, B.; Reine, J.; Rylance, J.; Zaidi, S.; Soares-Schanoski, A.; Connor, V.; Collins, A.M.; Schlitzer, A.; Nikolaou, E.; et al. Nasal Pneumococcal Density Is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens. Am. J. Respir. Crit. Care Med. 2020, 201, 335–347. [Google Scholar] [CrossRef]
  131. Ferreira, D.M.; Neill, D.R.; Bangert, M.; Gritzfeld, J.F.; Green, N.; Wright, A.K.; Pennington, S.H.; Bricio-Moreno, L.; Moreno, A.T.; Miyaji, E.N.; et al. Controlled human infection and rechallenge with Streptococcus pneumoniae reveals the protective efficacy of carriage in healthy adults. Am. J. Respir. Crit. Care Med. 2013, 187, 855–864. [Google Scholar] [CrossRef][Green Version]
  132. Goncalves, V.M.; Kaneko, K.; Solorzano, C.; MacLoughlin, R.; Saleem, I.; Miyaji, E.N. Progress in mucosal immunization for protection against pneumococcal pneumonia. Expert Rev. Vaccines 2019, 18, 781–792. [Google Scholar] [CrossRef]
  133. Mutsch, M.; Zhou, W.; Rhodes, P.; Bopp, M.; Chen, R.T.; Linder, T.; Spyr, C.; Steffen, R. Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. N. Engl. J. Med. 2004, 350, 896–903. [Google Scholar] [CrossRef] [PubMed][Green Version]
  134. Lewis, D.J.; Huo, Z.; Barnett, S.; Kromann, I.; Giemza, R.; Galiza, E.; Woodrow, M.; Thierry-Carstensen, B.; Andersen, P.; Novicki, D.; et al. Transient facial nerve paralysis (Bell’s palsy) following intranasal delivery of a genetically detoxified mutant of Escherichia coli heat labile toxin. PLoS ONE 2009, 4, e6999. [Google Scholar] [CrossRef]
  135. Zaman, M.; Ozberk, V.; Langshaw, E.L.; McPhun, V.; Powell, J.L.; Phillips, Z.N.; Ho, M.F.; Calcutt, A.; Batzloff, M.R.; Toth, I.; et al. Novel platform technology for modular mucosal vaccine that protects against streptococcus. Sci. Rep. 2016, 6, 39274. [Google Scholar] [CrossRef] [PubMed][Green Version]
  136. Ickovic, M.R.; Relyveld, E.H.; Henocq, E.; David, B.; Marie, F.N. Calcium-phosphate-adjuvanted allergens: Total and specific IgE levels before and after immunotherapy with house dust and Dermatophagoides pteronyssinus extracts. Ann. Immunol. 1983, 134D, 385–398. [Google Scholar] [CrossRef]
  137. He, Q.; Mitchell, A.R.; Johnson, S.L.; Wagner-Bartak, C.; Morcol, T.; Bell, S.J. Calcium phosphate nanoparticle adjuvant. Clin. Diagn. Lab. Immunol. 2000, 7, 899–903. [Google Scholar] [CrossRef] [PubMed][Green Version]
  138. Mudgal, R.; Nehul, S.; Tomar, S. Prospects for mucosal vaccine: Shutting the door on SARS-CoV-2. Hum. Vaccines Immunother. 2020, 16, 2921–2931. [Google Scholar] [CrossRef]
  139. Sokolova, V.; Knuschke, T.; Kovtun, A.; Buer, J.; Epple, M.; Westendorf, A.M. The use of calcium phosphate nanoparticles encapsulating Toll-like receptor ligands and the antigen hemagglutinin to induce dendritic cell maturation and T cell activation. Biomaterials 2010, 31, 5627–5633. [Google Scholar] [CrossRef]
  140. Lin, Y.; Wang, X.; Huang, X.; Zhang, J.; Xia, N.; Zhao, Q. Calcium phosphate nanoparticles as a new generation vaccine adjuvant. Expert Rev. Vaccines 2017, 16, 895–906. [Google Scholar] [CrossRef]
  141. Relyveld, E.H.; Ickovic, M.R.; Henocq, E.; Garcelon, M. Calcium phosphate adjuvanted allergens. Ann. Allergy 1985, 54, 521–529. [Google Scholar] [PubMed]
  142. Masson, J.D.; Thibaudon, M.; Belec, L.; Crepeaux, G. Calcium phosphate: A substitute for aluminum adjuvants? Expert Rev. Vaccines 2017, 16, 289–299. [Google Scholar] [CrossRef] [PubMed]
  143. Kodama, S.; Abe, N.; Hirano, T.; Suzuki, M. Safety and efficacy of nasal application of CpG oligodeoxynucleotide as a mucosal adjuvant. Laryngoscope 2006, 116, 331–335. [Google Scholar] [CrossRef] [PubMed]
  144. Bode, C.; Zhao, G.; Steinhagen, F.; Kinjo, T.; Klinman, D.M. CpG DNA as a vaccine adjuvant. Expert Rev. Vaccines 2011, 10, 499–511. [Google Scholar] [CrossRef] [PubMed][Green Version]
  145. Merkus, F.W.; Verhoef, J.C.; Schipper, N.G.; Marttin, E. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv. Drug Deliv. Rev. 1998, 29, 13–38. [Google Scholar] [CrossRef]
  146. Beule, A.G. Physiology and pathophysiology of respiratory mucosa of the nose and the paranasal sinuses. GMS Curr. Top. Otorhinolaryngol. Head Neck Surg. 2010, 9, Doc07. [Google Scholar] [CrossRef]
  147. Shekhar, S.; Khan, R.; Schenck, K.; Petersen, F.C. Intranasal Immunization with the Commensal Streptococcus mitis Confers Protective Immunity against Pneumococcal Lung Infection. Appl. Environ. Microbiol. 2019, 85. [Google Scholar] [CrossRef][Green Version]
  148. Tada, R.; Suzuki, H.; Takahashi, S.; Negishi, Y.; Kiyono, H.; Kunisawa, J.; Aramaki, Y. Nasal vaccination with pneumococcal surface protein A in combination with cationic liposomes consisting of DOTAP and DC-chol confers antigen-mediated protective immunity against Streptococcus pneumoniae infections in mice. Int. Immunopharmacol. 2018, 61, 385–393. [Google Scholar] [CrossRef]
  149. Xu, J.H.; Dai, W.J.; Chen, B.; Fan, X.Y. Mucosal immunization with PsaA protein, using chitosan as a delivery system, increases protection against acute otitis media and invasive infection by Streptococcus pneumoniae. Scand. J. Immunol. 2015, 81, 177–185. [Google Scholar] [CrossRef]
  150. Suzuki, H.; Watari, A.; Hashimoto, E.; Yonemitsu, M.; Kiyono, H.; Yagi, K.; Kondoh, M.; Kunisawa, J. C-Terminal Clostridium perfringens Enterotoxin-Mediated Antigen Delivery for Nasal Pneumococcal Vaccine. PLoS ONE 2015, 10, e0126352. [Google Scholar] [CrossRef] [PubMed][Green Version]
  151. Rodrigues, T.C.; Oliveira, M.L.S.; Soares-Schanoski, A.; Chavez-Rico, S.L.; Figueiredo, D.B.; Goncalves, V.M.; Ferreira, D.M.; Kunda, N.K.; Saleem, I.Y.; Miyaji, E.N. Mucosal immunization with PspA (Pneumococcal surface protein A)-adsorbed nanoparticles targeting the lungs for protection against pneumococcal infection. PLoS ONE 2018, 13, e0191692. [Google Scholar] [CrossRef][Green Version]
  152. Salha, D.; Szeto, J.; Myers, L.; Claus, C.; Sheung, A.; Tang, M.; Ljutic, B.; Hanwell, D.; Ogilvie, K.; Ming, M.; et al. Neutralizing antibodies elicited by a novel detoxified pneumolysin derivative, PlyD1, provide protection against both pneumococcal infection and lung injury. Infect. Immun. 2012, 80, 2212–2220. [Google Scholar] [CrossRef][Green Version]
  153. Yuan, Z.Q.; Lv, Z.Y.; Gan, H.Q.; Xian, M.; Zhang, K.X.; Mai, J.Y.; Yu, X.B.; Wu, Z.D. Intranasal immunization with autolysin (LytA) in mice model induced protection against five prevalent Streptococcus pneumoniae serotypes in China. Immunol. Res. 2011, 51, 108–115. [Google Scholar] [CrossRef]
  154. Nguyen, C.T.; Kim, S.Y.; Kim, M.S.; Lee, S.E.; Rhee, J.H. Intranasal immunization with recombinant PspA fused with a flagellin enhances cross-protective immunity against Streptococcus pneumoniae infection in mice. Vaccine 2011, 29, 5731–5739. [Google Scholar] [CrossRef] [PubMed]
  155. Wu, K.; Yao, R.; Wang, H.; Pang, D.; Liu, Y.; Xu, H.; Zhang, S.; Zhang, X.; Yin, Y. Mucosal and systemic immunization with a novel attenuated pneumococcal vaccine candidate confer serotype independent protection against Streptococcus pneumoniae in mice. Vaccine 2014, 32, 4179–4188. [Google Scholar] [CrossRef] [PubMed]
  156. Jwa, M.Y.; Jeong, S.; Ko, E.B.; Kim, A.R.; Kim, H.Y.; Kim, S.K.; Seo, H.S.; Yun, C.H.; Han, S.H. Gamma-irradiation of Streptococcus pneumoniae for the use as an immunogenic whole cell vaccine. J. Microbiol. 2018, 56, 579–585. [Google Scholar] [CrossRef]
  157. Babb, R.; Chen, A.; Hirst, T.R.; Kara, E.E.; McColl, S.R.; Ogunniyi, A.D.; Paton, J.C.; Alsharifi, M. Intranasal vaccination with gamma-irradiated Streptococcus pneumoniae whole-cell vaccine provides serotype-independent protection mediated by B-cells and innate IL-17 responses. Clin. Sci. 2016, 130, 697–710. [Google Scholar] [CrossRef][Green Version]
Figure 1. Vaccines for pneumococcal disease derived from polysaccharide content of S. pneumoniae to generate either pneumococcal polysaccharide vaccine (PPSV) or pneumococcal conjugate vaccine (PCV) clinical options. The liposomal encapsulation of polysaccharide (LEPS) vaccine platform is presented in comparison.
Figure 1. Vaccines for pneumococcal disease derived from polysaccharide content of S. pneumoniae to generate either pneumococcal polysaccharide vaccine (PPSV) or pneumococcal conjugate vaccine (PCV) clinical options. The liposomal encapsulation of polysaccharide (LEPS) vaccine platform is presented in comparison.
Vaccines 09 00589 g001
Table 1. Main Respiratory Illnesses and Their Treatment Methods.
Table 1. Main Respiratory Illnesses and Their Treatment Methods.
DiseaseInfectious AgentNotesTherapeutic/Preventative OptionsReferences
InfluenzaPrimarily Influenza A virus
  • Millions of global cases and hundreds of thousands of deaths annually
  • Responsible for historic (Spanish, Asian, Russian, Hong Kong Flu) and more recent (swine and avian flu) outbreaks
  • Neuraminidase inhibitors (Tamiflu)
  • Seasonal and dedicated vaccines
  • Cap-dependent endonuclease inhibitor
Pneumococcal DiseaseStreptococcus
  • Millions of global deaths annually
  • Affects young, elderly, resource-limited groups
  • Commonly synergistic with influenza
  • Antibiotics
  • Polysaccharide conjugate and non-conjugate vaccines
Whooping Cough (Pertussis)Bordetella
  • Part of common DTaP vaccine (diphtheria-tetanus-pertussis)
  • Millions of global cases annually
  • Antibiotics
  • Vaccine
  • Global incidence in millions
  • Complicated by latent and drug resistant forms
  • Antibiotics
  • BCG vaccine
Coronavirus-based diseasesVarious viruses (including SARS-CoV-2)
  • Previous SARS (2002) and MERS (2012) outbreaks
  • Current COVID-19 pandemic
  • Recent COVID-19 vaccines
  • Antiviral drugs and advanced therapeutics (including antibody treatments)
Table 2. Intranasal Vaccine Delivery for Respiratory Tract Diseases.
Table 2. Intranasal Vaccine Delivery for Respiratory Tract Diseases.
DiseaseNumber of IN Applications
(Identified Using the PubMed Search Engine for Indicated Year)
Pneumococcal Disease42932
Whooping Cough13031
Table 3. Range of IN Approaches.
Table 3. Range of IN Approaches.
IN Method UsedRationalTimes TestedDisease ApplicationReference
Dry Powder
-Inulin nanoparticles
-Chitosan nanospheres
  • Highly stable
  • Extended residence time
(Influenza A virus)
Intranasal Instillation
-Stabilized protein subunit
-Inert bacterial spores
-Bacterium-like particles
  • Simple and easy form of delivery
  • Low cost
7Pneumonia (Actinobacillus pleuropneumoniae)[45]
Tuberculosis (M. tuberculosis)[46,47,48]
Pneumococcal Disease (S. pneumoniae)[49]
(Influenza A virus)
-Adenovirus vector-based
  • Efficient delivery of materials
  • Targets lower respiratory tract
(Influenza A virus)
Nasal Gel
-Cationic cholesteryl pullulan
  • Reduction in nasal clearance
  • Sustained release
1Pneumococcal Disease (S. pneumoniae)[53]
Table 4. Intranasal Vaccine Studies for Pneumococcal Disease.
Table 4. Intranasal Vaccine Studies for Pneumococcal Disease.
Vaccine CategoryAntigen Content (IN Method)Adjuvant IncludedReference
Subunit VaccineS. pneumoniae serotype 4 capsule (Intranasal Instillation)No adjuvant[147]
Recombinant PspA (Nasal Gel)No adjuvant[53]
Recombinant PspA (Intranasal Instillation)DOTAP/DC-chol liposome[148]
Recombinant PspA (Intranasal Instillation)Chitosan[149]
Recombinant PspA (Intranasal Instillation)Clostridium perfringens enterotoxin (C-CPE)[150]
Recombinant PspA/BLP (Intranasal Instillation)No adjuvant[49]
Recombinant PspA (nanoparticle absorbed) (Intranasal Instillation)(PGA-co-PDL) nanoparticles[151]
Recombinant PLY (Intranasal Instillation)Aluminum hydroxide[152]
Recombinant LytA (Intranasal Instillation)CpG oligodeoxynucleotides[153]
Recombinant PspA/FlaB fusion (Intranasal Instillation)Recombinant FlaB[154]
Live and/or AttenuatedS. pneumoniae Y1 (Intranasal Instillation)Cholera Toxin[155]
S. pneumoniae serotype 19F/23A/35B (Intranasal Instillation)No adjuvant[124]
S. pneumoniae serotype 19F (Intranasal Instillation)No adjuvant[125]
S. pneumoniae serotype 23F (Intranasal Instillation)No adjuvant[129]
S. pneumoniae serotype 6B (Intranasal instillation)No adjuvant[130]
S. pneumoniae serotype 6B (Intranasal instillation)No adjuvant[131]
Inactivated/KilledGamma irradiated nonencapsulated S. pneumoniae TIGR4 (Intranasal Instillation)Cholera toxin[156]
Gamma irradiated whole cell S. pneumoniae (Intranasal Instillation)No adjuvant[157]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Walkowski, W.; Bassett, J.; Bhalla, M.; Pfeifer, B.A.; Ghanem, E.N.B. Intranasal Vaccine Delivery Technology for Respiratory Tract Disease Application with a Special Emphasis on Pneumococcal Disease. Vaccines 2021, 9, 589.

AMA Style

Walkowski W, Bassett J, Bhalla M, Pfeifer BA, Ghanem ENB. Intranasal Vaccine Delivery Technology for Respiratory Tract Disease Application with a Special Emphasis on Pneumococcal Disease. Vaccines. 2021; 9(6):589.

Chicago/Turabian Style

Walkowski, William, Justin Bassett, Manmeet Bhalla, Blaine A. Pfeifer, and Elsa N. Bou Ghanem. 2021. "Intranasal Vaccine Delivery Technology for Respiratory Tract Disease Application with a Special Emphasis on Pneumococcal Disease" Vaccines 9, no. 6: 589.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop