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Considerations for the development of a prophylactic vaccine for Acinetobacter baumannii
Vaccine 32 (2014) 2534–2536
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Commentary
Considerations for the development of a prophylactic vaccine for Acinetobacter baumannii Jerónimo Pachón, Michael J. McConnell ∗ Biomedical Institute of Sevilla (IBiS), University Hospital Virgen del Rocío/CSIC/University of Sevilla, 41013 Sevilla, Spain
a r t i c l e
i n f o
Article history: Received 16 January 2013 Received in revised form 8 October 2013 Accepted 22 October 2013 Available online 1 November 2013 Keywords: Acinetobacter baumannii Antibiotic resistance Vaccine
Nosocomial infections caused by Acinetobacter baumannii have become a serious public health problem. This has become especially apparent due to the global emergence of multidrug resistant (MDR) strains of A. baumannii during the previous three decades. MDR A. baumannii is resistant to antibiotics from multiple classes, making the clinical management of infections caused by these strains increasingly difficult. Unfortunately, in spite of the increasing prevalence of infections caused by MDR A. baumannii, interest in the development of antibiotics for the treatment of these infections by the pharmaceutical industry has waned [1]. In this context, the implementation of prophylactic vaccination, both active and passive, for the prevention of infections caused by A. baumannii may represent a cost-effective approach for reducing the clinical and economic burden of infections caused by this pathogen. In the present commentary, we discuss considerations for the development of these vaccines, addressing both the patient populations that could benefit from vaccination and aspects related to vaccine design. In addition, we summarize the studies that have been performed which describe experimental vaccines for A. baumannii. 1. Prophylactic vaccination against A. baumannii: who, how, and when A. baumannii can produce multiple infection types including, but not limited to pneumonia, bloodstream infections, meningitis,
∗ Corresponding author at: Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Laboratorio 208, Avenida Manuel Siurot s/n, 41013 Sevilla, Spain. Tel.: +34 955923104. E-mail address: [email protected] (M.J. McConnell). 0264-410X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.10.064
skin and soft tissue infections and urinary tract infections [2]. Although community-acquired infections have been reported, infections caused by A. baumannii are mostly acquired in the hospital setting. This is a critical point when considering which populations would benefit from prophylactic vaccination against infections caused by A. baumannii, as the targeted vaccination of hospitalized patients or patients at risk of being hospitalized who have risk factors for acquiring infections by A. baumannii would likely be the most cost-effective approach. Based on this idea, we propose four patient populations that may benefit from vaccination. The identification of these at-risk groups is based on published literature identifying risk factors for the acquisition of A. baumannii infection. However, as with all vaccines, local epidemiology will ultimately determine whether or not a particular patient is at risk, given that the prevalence of A. baumannii infections varies widely depending on geographic location and healthcare center. A. baumannii is a frequent cause of ventilator-associated pneumonia (VAP), making patients who require mechanical ventilation at the time of presentation and patients who have a high likelihood of needing mechanical ventilation during their clinical course potential targets for vaccination. This includes patients who undergo programmed surgical procedures, such as cardiac, neurologic and pulmonary operations, for which mechanical ventilation is a part of routine post-operative care. In addition, individuals admitted urgently who may require mechanical ventilation are also at-risk for A. baumannii VAP. These may include patients with neurotrauma, patients admitted with cerebrovascular accident with respiratory complications, and patients admitted with severe respiratory insufficiency. A second group of patients that may benefit from vaccination are those at risk for acquiring nosocomial skin and soft tissue infections caused by A. baumannii. Individuals at risk for
J. Pachón, M.J. McConnell / Vaccine 32 (2014) 2534–2536
2535
Table 1 Antigens used in experimental Acinetobacter baumannii vaccines. Antigen
Results
References
Formalin-inactivated whole cells
Intramuscular/intranasal vaccination with or without an aluminum-based adjuvant, reduction in post-infection tissue bacterial loads, protection in a mouse model of sepsis, passive protection using antisera
[6,8]
Outer membrane complexes
Intramuscular vaccination with an aluminum-based adjuvant, reduction in post-infection tissue bacterial loads, protection in mouse model of sepsis, passive protection using antisera, treatment of infected mice with antisera
[5]
Outer membrane vesicles
Intramuscular vaccination with an aluminum-based adjuvant, reduction in post-infection tissue bacterial loads, protection in a mouse model of sepsis
[7]
Biofilm-associated protein (Bap)
Freund’s adjuvant, reduction in post-infection tissue bacterial loads, protection in a mouse model of sepsis
[9]
Poly-N-acetyl--(1–6)-glucosamine (PNAG)
Passive intranasal/intravenous immunization, opsonophagocytosis of A. baumannii with antisera, reduction in tissue bacterial loads after passive immunization in a mouse model of pneumonia
[3]
Trimeric autotransporter protein (Ata)
Passive intravenous immunization, opsonophagocytosis of A. baumannii with antisera, complement-dependant bactericidal activity of antisera, reduction in tissue bacterial loads after passive immunization in a mouse model of pneumonia
[4]
Outer membrane protein A (OmpA)
Subcutaneous vaccination with an aluminum hydroxide adjuvant, protection in a diabetic mouse model of sepsis, opsonophagocytosis of A. baumannii with antisera, protection after passive immunization
[10]
K1 capsular polysaccharide
Subcutaneous passive immunization in a mouse soft tissue infection model, decrease in tissue bacterial loads
[11]
this type of infection include patients that have sustained extensive burn injury, patients undergoing complex abdominal surgical procedures, and military personnel sustaining war-related trauma. The latter group is also at risk for A. baumannii osteomyelitis, underscoring the potential benefit of immunizing military personnel. A third target population for immunization is patients who are at risk for A. baumannii meningitis. These infections are primarily associated with neurosurgical operations, raising the possibility that patients undergoing both programmed and emergent neurosurgical procedures in situations where A. baumannii infection could occur may benefit from vaccination. A final possibility is the vaccination of patients admitted to an intensive care unit in the context of an outbreak of a difficult-to-treat clone of A. baumannii. Clearly a decision on whether or not to employ such a strategy must take into account local epidemiology and antibiotic resistance profiles. However, given the propensity of this organism to produce localized outbreaks, this approach may be warranted in some cases. In the clinical scenarios mentioned here, prophylactic vaccination my serve to prevent initial colonization events, which in many cases are thought to precede infection. Due to the fact that some of the target populations for vaccination include critically ill patients with weakened immune systems, a crucial issue will be the ability of a vaccine to elicit a protective response in this context. Once at-risk patient populations have been identified, it must be determined when and how these patients should be vaccinated. A key factor is whether an active or a passive immunization strategy would be more appropriate given the clinical scenario. Although active and passive immunization differ with respect to the pharmacologic agent that is administered and when and how it is dosed, there are some general themes which appear evident. Individuals for whom the risk of acquiring an infection caused by A. baumannii can be foreseen could be actively immunized with enough time to allow for a protective immune response to be elicited before that individual is exposed to A. baumannii. This would include patients undergoing programmed surgical procedures and military personnel. Active immunization has a proven track record against regarding both safety and efficacy for bacterial diseases, and compared to passive immunotherapy approaches based on the administration of antibody preparations (e.g. monoclonal antibodies) it is relatively inexpensive.
However, patients for whom the risk of exposure cannot be foreseen, such as patients sustaining traumatic injuries or patients undergoing emergent surgery, present a more difficult scenario. In these cases there may not be enough lead time for an active vaccine to produce a protective response before the individual is exposed to A. baumannii, making passive immunization a logical approach in these cases. Although passive immunization has the potential to provide almost instantaneous protective immunity, its ability to prevent bacterial diseases in the clinical setting has yet to be determined. 2. Aspects related to vaccine design Identification of the A. baumannii infections that will be targeted by a prophylactic vaccine and the characteristics of the patients that acquire these types of infections can be used to guide the development of an effective vaccine. As mentioned above, A. baumannii produces a diversity of infection types. For this reason, an ideal vaccine would be capable of protecting against all A. baumannii infections. Given the infections described above, this may require that the vaccine produces both a systemic and a mucosal response. In addition, the contributions of the cellular and humoral arms of the immune response have yet to be fully characterized. Studies performed in experimental models of A. baumannii infection have already begun to shed some light onto this question as it has been shown that that the passive transfer of serum raised against A. baumannii antigens is sufficient for providing protection against infection [3–6], indicating that passive vaccination approaches based on the administration of antibodies may be effective. Clearly these aspects will have to be considered during the development of a vaccine and when determining the route of vaccine administration. Another important point to consider is the time that elapses between immunization and achieving protective immunity. This is of critical importance since in many cases the risk for exposure to A. baumannii cannot be foreseen. An ideal vaccine would induce protective immunity shortly after a single administration. This may be less problematic when passive immunization approaches are employed, however for active vaccination a vaccine that requires a lengthy administration regimen or is slow to induce protective
2536
J. Pachón, M.J. McConnell / Vaccine 32 (2014) 2534–2536
immunity may not be effective in cases that require the rapid elicitation of protective immunity. Aspects related to antigen design and adjuvant selection will undoubtedly play a role in determining the kinetics of the immune response. A final consideration is the selection of an appropriate antigen or antigens for the development of active and passive vaccination strategies. In this case, many of the same aspects that must be considered for the development of vaccines against other bacterial pathogens apply. An ideal antigen would be present on the bacterial cell surface, expressed during human infection, present in the majority of A. baumannii strains and highly conserved at the amino acid level, if the antigen is a protein. A handful of reports have begun to evaluate various antigens in experimental animal models of A. baumannii infection. The antigens used in theses studies and the results obtained with these antigens are summarized in Table 1. Vaccines consisting of inactivated whole cells, outer membrane vesicles and outer membrane extracts have been shown to elicit antibodies against multiple bacterial antigens and provide protection against infection in mouse models of sepsis [5–8]. However, due to the complexity of these multicomponent vaccines, it may be difficult to standardize vaccine doses between production lots, and their high lipopolysaccharide content may be above the levels permissible for use in humans. Subunit vaccines consisting of purified outer membrane proteins or surface polysaccharides have also been shown to be effective in providing active or passive immunity in experimental models of infection (Table 1) [3,4,9–11]. These vaccine formulations may have the advantage of not being hindered by the regulatory issues that could be faced by the multicomponent vaccines described above. For single subunit antigens, studies addressing their presence in epidemiologically diverse collections of A. baumannii strains will be critical for supporting their further development. An approach which may incorporate the advantage of both multicomponent vaccines and single subunit vaccines is the use of defined polyvalent vaccines that consist of multiple subunit antigens. In summary, the health burden caused by A. baumannii infections has reached a point were prophylactic vaccination may be warranted in some cases. Vaccine development for A. baumannii has already begun, highlighting the importance of defining characteristics of the target patient populations and the desired immune response that can be used to guide effective vaccine design.
Acknowledgements This work was supported by the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III – co-financed by European Development Regional Fund “A way to achieve Europe” ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015) and the Consejería de Salud y Bienestar de la Junta de Andalucía (CP11/00314). M.J.M. is supported by the Subprograma Miguel Servet from the Ministerio de Economía y Competitividad of Spain. References [1] Cooper MA, Shlaes D. Fix the antibiotics pipeline. Nature 2011;472(April (7341)):32. [2] McConnell MJ, Actis L, Pachón J. Acinetobacter baumannii: human infections, factors contributing to pathogenesis and animal models. FEMS Microbiol Rev 2013;(March (2)):130–55. [3] Bentancor LV, O’Malley JM, Bozkurt-Guzel C, Pier GB, Maira-Litran T. Poly-N-acetyl-beta-(1–6)-glucosamine is a target for protective immunity against Acinetobacter baumannii infections. Infect Immun 2012;80(February (2)):651–6. [4] Bentancor LV, Routray A, Bozkurt-Guzel C, Camacho-Peiro A, Pier GB, MairaLitran T. Evaluation of the trimeric autotransporter Ata as a vaccine candidate against Acinetobacter baumannii infections. Infect Immun 2012;80(October (10)):3381–8. [5] McConnell MJ, Domínguez-Herrera J, Smani Y, López-Rojas R, Docobo-Pérez F, Pachón J. Vaccination with outer membrane complexes elicits rapid protective immunity to multidrug-resistant Acinetobacter baumannii. Infect Immun 2011;79(January (1)):518–26. [6] McConnell MJ, Pachón J. Active and passive immunization against Acinetobacter baumannii using an inactivated whole cell vaccine. Vaccine 2010;29(December (1)):1–5. [7] McConnell MJ, Rumbo C, Bou G, Pachón J. Outer membrane vesicles as an acellular vaccine against Acinetobacter baumannii. Vaccine 2011;29(August (34)):5705–10. [8] Harris G, Kuo Lee R, Lam CK, Kanzaki G, Patel GB, Xu HH, et al. A mouse model of Acinetobacter baumannii-associated pneumonia using a clinically isolated hypervirulent strain. Antimicrob Agents Chemother 2013;57(August (8)):3601–13. [9] Fattahian Y, Rasooli I, Mousavi Gargari SL, Rahbar MR, Darvish Alipour Astaneh S, Amani J. Protection against Acinetobacter baumannii infection via its functional deprivation of biofilm associated protein (Bap). Microb Pathog 2011;51(December (6)):402–6. [10] Luo G, Lin L, Ibrahim AS, Baquir B, Pantapalangkoor P, Bonomo RA, et al. Active and passive immunization protects against lethal, extreme drug resistantAcinetobacter baumannii infection. PLoS One 2012;7(1):e29446. [11] Russo TA, Beanan JM, Olson R, MacDonald U, Cox AD, St Michael F, et al. The K1 capsular polysaccharide from Acinetobacter baumannii is a potential therapeutic target via passive immunization. Infect Immun 2013;81(March (3)):915–22.
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Commentary
Considerations for the development of a prophylactic vaccine for Acinetobacter baumannii Jerónimo Pachón, Michael J. McConnell ∗ Biomedical Institute of Sevilla (IBiS), University Hospital Virgen del Rocío/CSIC/University of Sevilla, 41013 Sevilla, Spain
a r t i c l e
i n f o
Article history: Received 16 January 2013 Received in revised form 8 October 2013 Accepted 22 October 2013 Available online 1 November 2013 Keywords: Acinetobacter baumannii Antibiotic resistance Vaccine
Nosocomial infections caused by Acinetobacter baumannii have become a serious public health problem. This has become especially apparent due to the global emergence of multidrug resistant (MDR) strains of A. baumannii during the previous three decades. MDR A. baumannii is resistant to antibiotics from multiple classes, making the clinical management of infections caused by these strains increasingly difficult. Unfortunately, in spite of the increasing prevalence of infections caused by MDR A. baumannii, interest in the development of antibiotics for the treatment of these infections by the pharmaceutical industry has waned [1]. In this context, the implementation of prophylactic vaccination, both active and passive, for the prevention of infections caused by A. baumannii may represent a cost-effective approach for reducing the clinical and economic burden of infections caused by this pathogen. In the present commentary, we discuss considerations for the development of these vaccines, addressing both the patient populations that could benefit from vaccination and aspects related to vaccine design. In addition, we summarize the studies that have been performed which describe experimental vaccines for A. baumannii. 1. Prophylactic vaccination against A. baumannii: who, how, and when A. baumannii can produce multiple infection types including, but not limited to pneumonia, bloodstream infections, meningitis,
∗ Corresponding author at: Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Laboratorio 208, Avenida Manuel Siurot s/n, 41013 Sevilla, Spain. Tel.: +34 955923104. E-mail address: [email protected] (M.J. McConnell). 0264-410X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.10.064
skin and soft tissue infections and urinary tract infections [2]. Although community-acquired infections have been reported, infections caused by A. baumannii are mostly acquired in the hospital setting. This is a critical point when considering which populations would benefit from prophylactic vaccination against infections caused by A. baumannii, as the targeted vaccination of hospitalized patients or patients at risk of being hospitalized who have risk factors for acquiring infections by A. baumannii would likely be the most cost-effective approach. Based on this idea, we propose four patient populations that may benefit from vaccination. The identification of these at-risk groups is based on published literature identifying risk factors for the acquisition of A. baumannii infection. However, as with all vaccines, local epidemiology will ultimately determine whether or not a particular patient is at risk, given that the prevalence of A. baumannii infections varies widely depending on geographic location and healthcare center. A. baumannii is a frequent cause of ventilator-associated pneumonia (VAP), making patients who require mechanical ventilation at the time of presentation and patients who have a high likelihood of needing mechanical ventilation during their clinical course potential targets for vaccination. This includes patients who undergo programmed surgical procedures, such as cardiac, neurologic and pulmonary operations, for which mechanical ventilation is a part of routine post-operative care. In addition, individuals admitted urgently who may require mechanical ventilation are also at-risk for A. baumannii VAP. These may include patients with neurotrauma, patients admitted with cerebrovascular accident with respiratory complications, and patients admitted with severe respiratory insufficiency. A second group of patients that may benefit from vaccination are those at risk for acquiring nosocomial skin and soft tissue infections caused by A. baumannii. Individuals at risk for
J. Pachón, M.J. McConnell / Vaccine 32 (2014) 2534–2536
2535
Table 1 Antigens used in experimental Acinetobacter baumannii vaccines. Antigen
Results
References
Formalin-inactivated whole cells
Intramuscular/intranasal vaccination with or without an aluminum-based adjuvant, reduction in post-infection tissue bacterial loads, protection in a mouse model of sepsis, passive protection using antisera
[6,8]
Outer membrane complexes
Intramuscular vaccination with an aluminum-based adjuvant, reduction in post-infection tissue bacterial loads, protection in mouse model of sepsis, passive protection using antisera, treatment of infected mice with antisera
[5]
Outer membrane vesicles
Intramuscular vaccination with an aluminum-based adjuvant, reduction in post-infection tissue bacterial loads, protection in a mouse model of sepsis
[7]
Biofilm-associated protein (Bap)
Freund’s adjuvant, reduction in post-infection tissue bacterial loads, protection in a mouse model of sepsis
[9]
Poly-N-acetyl--(1–6)-glucosamine (PNAG)
Passive intranasal/intravenous immunization, opsonophagocytosis of A. baumannii with antisera, reduction in tissue bacterial loads after passive immunization in a mouse model of pneumonia
[3]
Trimeric autotransporter protein (Ata)
Passive intravenous immunization, opsonophagocytosis of A. baumannii with antisera, complement-dependant bactericidal activity of antisera, reduction in tissue bacterial loads after passive immunization in a mouse model of pneumonia
[4]
Outer membrane protein A (OmpA)
Subcutaneous vaccination with an aluminum hydroxide adjuvant, protection in a diabetic mouse model of sepsis, opsonophagocytosis of A. baumannii with antisera, protection after passive immunization
[10]
K1 capsular polysaccharide
Subcutaneous passive immunization in a mouse soft tissue infection model, decrease in tissue bacterial loads
[11]
this type of infection include patients that have sustained extensive burn injury, patients undergoing complex abdominal surgical procedures, and military personnel sustaining war-related trauma. The latter group is also at risk for A. baumannii osteomyelitis, underscoring the potential benefit of immunizing military personnel. A third target population for immunization is patients who are at risk for A. baumannii meningitis. These infections are primarily associated with neurosurgical operations, raising the possibility that patients undergoing both programmed and emergent neurosurgical procedures in situations where A. baumannii infection could occur may benefit from vaccination. A final possibility is the vaccination of patients admitted to an intensive care unit in the context of an outbreak of a difficult-to-treat clone of A. baumannii. Clearly a decision on whether or not to employ such a strategy must take into account local epidemiology and antibiotic resistance profiles. However, given the propensity of this organism to produce localized outbreaks, this approach may be warranted in some cases. In the clinical scenarios mentioned here, prophylactic vaccination my serve to prevent initial colonization events, which in many cases are thought to precede infection. Due to the fact that some of the target populations for vaccination include critically ill patients with weakened immune systems, a crucial issue will be the ability of a vaccine to elicit a protective response in this context. Once at-risk patient populations have been identified, it must be determined when and how these patients should be vaccinated. A key factor is whether an active or a passive immunization strategy would be more appropriate given the clinical scenario. Although active and passive immunization differ with respect to the pharmacologic agent that is administered and when and how it is dosed, there are some general themes which appear evident. Individuals for whom the risk of acquiring an infection caused by A. baumannii can be foreseen could be actively immunized with enough time to allow for a protective immune response to be elicited before that individual is exposed to A. baumannii. This would include patients undergoing programmed surgical procedures and military personnel. Active immunization has a proven track record against regarding both safety and efficacy for bacterial diseases, and compared to passive immunotherapy approaches based on the administration of antibody preparations (e.g. monoclonal antibodies) it is relatively inexpensive.
However, patients for whom the risk of exposure cannot be foreseen, such as patients sustaining traumatic injuries or patients undergoing emergent surgery, present a more difficult scenario. In these cases there may not be enough lead time for an active vaccine to produce a protective response before the individual is exposed to A. baumannii, making passive immunization a logical approach in these cases. Although passive immunization has the potential to provide almost instantaneous protective immunity, its ability to prevent bacterial diseases in the clinical setting has yet to be determined. 2. Aspects related to vaccine design Identification of the A. baumannii infections that will be targeted by a prophylactic vaccine and the characteristics of the patients that acquire these types of infections can be used to guide the development of an effective vaccine. As mentioned above, A. baumannii produces a diversity of infection types. For this reason, an ideal vaccine would be capable of protecting against all A. baumannii infections. Given the infections described above, this may require that the vaccine produces both a systemic and a mucosal response. In addition, the contributions of the cellular and humoral arms of the immune response have yet to be fully characterized. Studies performed in experimental models of A. baumannii infection have already begun to shed some light onto this question as it has been shown that that the passive transfer of serum raised against A. baumannii antigens is sufficient for providing protection against infection [3–6], indicating that passive vaccination approaches based on the administration of antibodies may be effective. Clearly these aspects will have to be considered during the development of a vaccine and when determining the route of vaccine administration. Another important point to consider is the time that elapses between immunization and achieving protective immunity. This is of critical importance since in many cases the risk for exposure to A. baumannii cannot be foreseen. An ideal vaccine would induce protective immunity shortly after a single administration. This may be less problematic when passive immunization approaches are employed, however for active vaccination a vaccine that requires a lengthy administration regimen or is slow to induce protective
2536
J. Pachón, M.J. McConnell / Vaccine 32 (2014) 2534–2536
immunity may not be effective in cases that require the rapid elicitation of protective immunity. Aspects related to antigen design and adjuvant selection will undoubtedly play a role in determining the kinetics of the immune response. A final consideration is the selection of an appropriate antigen or antigens for the development of active and passive vaccination strategies. In this case, many of the same aspects that must be considered for the development of vaccines against other bacterial pathogens apply. An ideal antigen would be present on the bacterial cell surface, expressed during human infection, present in the majority of A. baumannii strains and highly conserved at the amino acid level, if the antigen is a protein. A handful of reports have begun to evaluate various antigens in experimental animal models of A. baumannii infection. The antigens used in theses studies and the results obtained with these antigens are summarized in Table 1. Vaccines consisting of inactivated whole cells, outer membrane vesicles and outer membrane extracts have been shown to elicit antibodies against multiple bacterial antigens and provide protection against infection in mouse models of sepsis [5–8]. However, due to the complexity of these multicomponent vaccines, it may be difficult to standardize vaccine doses between production lots, and their high lipopolysaccharide content may be above the levels permissible for use in humans. Subunit vaccines consisting of purified outer membrane proteins or surface polysaccharides have also been shown to be effective in providing active or passive immunity in experimental models of infection (Table 1) [3,4,9–11]. These vaccine formulations may have the advantage of not being hindered by the regulatory issues that could be faced by the multicomponent vaccines described above. For single subunit antigens, studies addressing their presence in epidemiologically diverse collections of A. baumannii strains will be critical for supporting their further development. An approach which may incorporate the advantage of both multicomponent vaccines and single subunit vaccines is the use of defined polyvalent vaccines that consist of multiple subunit antigens. In summary, the health burden caused by A. baumannii infections has reached a point were prophylactic vaccination may be warranted in some cases. Vaccine development for A. baumannii has already begun, highlighting the importance of defining characteristics of the target patient populations and the desired immune response that can be used to guide effective vaccine design.
Acknowledgements This work was supported by the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III – co-financed by European Development Regional Fund “A way to achieve Europe” ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015) and the Consejería de Salud y Bienestar de la Junta de Andalucía (CP11/00314). M.J.M. is supported by the Subprograma Miguel Servet from the Ministerio de Economía y Competitividad of Spain. References [1] Cooper MA, Shlaes D. Fix the antibiotics pipeline. Nature 2011;472(April (7341)):32. [2] McConnell MJ, Actis L, Pachón J. Acinetobacter baumannii: human infections, factors contributing to pathogenesis and animal models. FEMS Microbiol Rev 2013;(March (2)):130–55. [3] Bentancor LV, O’Malley JM, Bozkurt-Guzel C, Pier GB, Maira-Litran T. Poly-N-acetyl-beta-(1–6)-glucosamine is a target for protective immunity against Acinetobacter baumannii infections. Infect Immun 2012;80(February (2)):651–6. [4] Bentancor LV, Routray A, Bozkurt-Guzel C, Camacho-Peiro A, Pier GB, MairaLitran T. Evaluation of the trimeric autotransporter Ata as a vaccine candidate against Acinetobacter baumannii infections. Infect Immun 2012;80(October (10)):3381–8. [5] McConnell MJ, Domínguez-Herrera J, Smani Y, López-Rojas R, Docobo-Pérez F, Pachón J. Vaccination with outer membrane complexes elicits rapid protective immunity to multidrug-resistant Acinetobacter baumannii. Infect Immun 2011;79(January (1)):518–26. [6] McConnell MJ, Pachón J. Active and passive immunization against Acinetobacter baumannii using an inactivated whole cell vaccine. Vaccine 2010;29(December (1)):1–5. [7] McConnell MJ, Rumbo C, Bou G, Pachón J. Outer membrane vesicles as an acellular vaccine against Acinetobacter baumannii. Vaccine 2011;29(August (34)):5705–10. [8] Harris G, Kuo Lee R, Lam CK, Kanzaki G, Patel GB, Xu HH, et al. A mouse model of Acinetobacter baumannii-associated pneumonia using a clinically isolated hypervirulent strain. Antimicrob Agents Chemother 2013;57(August (8)):3601–13. [9] Fattahian Y, Rasooli I, Mousavi Gargari SL, Rahbar MR, Darvish Alipour Astaneh S, Amani J. Protection against Acinetobacter baumannii infection via its functional deprivation of biofilm associated protein (Bap). Microb Pathog 2011;51(December (6)):402–6. [10] Luo G, Lin L, Ibrahim AS, Baquir B, Pantapalangkoor P, Bonomo RA, et al. Active and passive immunization protects against lethal, extreme drug resistantAcinetobacter baumannii infection. PLoS One 2012;7(1):e29446. [11] Russo TA, Beanan JM, Olson R, MacDonald U, Cox AD, St Michael F, et al. The K1 capsular polysaccharide from Acinetobacter baumannii is a potential therapeutic target via passive immunization. Infect Immun 2013;81(March (3)):915–22.