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Phage Pathogen Routeof
administration/animal
Dose Immunological
effects
Reference
host’s immune
system
Dufour et al. [43] have not only compared the inlammatory response of
phages to uninfected controls in healthy mice but also to antibiotics in acute
E.coli pneumonia in mice. In uninfected mice, both phage 536_P1 and
LM33_P1 did not signiicantly change the complete blood count compared to
the control, except that LM33_P1 reduced the lymphocyte count at 7 hours
post-administration but that returned to normal 10 hours after that. Phage
536_P1 elevated IFN-y, IL-12, MCP-1 and keratinocyte chemoattractant at
17 hours post-administration, whereas LM33_P1 showed no difference in the
control at any time point. Phage 536_P1 also decreased IL-6, IL-1β, TNF-α,
keratinocyte chemoattractant, and MCP-1 to similar levels to that achieved by
ceftriaxone, a commonly used antibiotic for pneumonia.
Intratracheal delivery of P.aeruginosa PAO1 and ilamentous phage Pf4
resulted in a reduction of CXCL1, IL-17, IL-1β, IL-17 and IL-10. However, the
pro-inlammatory cytokine, IL-12p40, was signiicantly higher at 48 hours
post-administration compared to PAO1-infection alone [44]. In contrast,
intranasal administration of a phage cocktail did not affect serum cytokines
such as IL-1a, IL-1b, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17A, TNF-a and G-CSF [8].
Similarly, intranasal instillation of phage PAK_P1 showed no signiicant
increase in cytokine production compared to the control except for IFN-y and
TNF-α [38]. Interestingly, PAK_P1 displayed immunophage synergy where it
relied on the host’s immune system to effectively resolve the bacterial
infection. This response is yet to be observed in other species of phages.
There is currently no literature investigating the adaptive responses of
phages in the lungs.
5 FormulationsandStability
Stability is of utmost importance for any drug candidate, whether it is a small
molecule or biologic. Instability affects the delivery of the correct dose and
bioavailability and can form degradants. The PhagoBurn trial failed to show a
clinical difference between phage therapy and standard-of-care treatment
due to the instability of the phages, which led to the administration of a
subtherapeutic dose [26]. This highlights another hurdle that phage therapy
must overcome to be actively used clinically. Recent research suggests that
adding a stabiliser to the formulation can minimise the loss of viability over
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long-term storage [45–47]. Naturally, the safety of these excipients must be
investigated before clinical use.
5.1 LiquidAerosols
The signiicance of the PhagoBurn trial rested on the fact that it was the irst
randomised controlled trial investigating a lytic phage cocktail that was
produced according to good manufacturing practice and was approved by
national health regulators in Belgium, France, and Switzerland. The shortfall
of the trial was due to the unexpected decline by 104–10
5
PFU/mL in titre
post-manufacturing, which resulted in a much lower than the expectedadministered dose of 10
6
PFU/mL [26]. Post-trial stability study
demonstrated that the initial titre reduction occurred 15
days after
manufacturing. A major conclusion of the trial was that decreasing the
number of phage types and improving the stability were needed for future
trials. As the therapy was intended for IV injection, the cocktail was a liquid
formulation that was thought to be stable under refrigeration [48, 49].
However, Duyvejonck et al. [46] recently conirmed that at 4 °C phages with a
high titre of 10
9
PFU/mL were relatively more stable than the 107 PFU/mL
stock. This demonstrated that phage titre decreases over time even when
stored refrigerated, especially at lower starting titres [50]. Although ancillary
stability testing prior to the PhagoBurn trial found that the individual phages
of the cocktail were very stable at a titre of ≥10
9
PFU/mL for over 24 months,
the authors reported that there was a 1000-fold reduction of the stock within
15
days of manufacture [26]. The starting overall titre of the cocktail was
10
9
PFU/mL, meaning that the average titre for each of the 12 phages was
8.3 × 107 PFU/mL, which was lower than that tested for their individual
stability. As discussed above, phage OMKO1 had synergy with ceftazidime in
treating MDR P.
aeruginosa infection [34]. Blazanin et al. [51] tested the effect
of various conditions, including elevated temperature, varying saline and
urea concentrations, that phages may encounter in vitro and in vivo to study
their stability. Interestingly, although moderate titre reduction was only
observed from 65 to 75 °C, the plaque morphology of all heat-treated phages
changed. Further investigation demonstrated that the growth ability of
phages was signiicantly decreased compared to the control regardless of the
duration of thermal exposure at 70 °C [51]. A change in plaque morphology
may not necessarily equate to a change in the phenotype of the phage, as
transmission electronic microscopy (TEM) of phages (TS3, TS6, TS13)
treated at 70 °C for 30 minutes showed no morphological difference
compared to the control [52]. On the other hand, phage OMKO1 may not be a
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thermally stable phage as phages TS3, TS6 and TS13 were speciically isolated
for their thermal-resistant properties [52]. Furthermore, urea stress
tolerance over time revealed that the survivability of phage OMKO1 was
unaffected at lower urea concentrations of 1–2 M and was not signiicantly
different to that without urea [51]. However, phage survival reduced quickly
over the 90 minutes in 3–4 M urea [51]. Unlike heat and high urea
concentrations, high saline concentrations did not impact phage infectivity
[51]. Phages Acibel004, PNM, 14/1, and ISP stored in normal saline at 4 °C at
10
9
PFU/mL for over 300 days showed no change in phage infectivity [46].
Since saline is commonly used in pharmaceutical products, stability in saline
makes it a viable vehicle for formulating therapeutic phages.
Liquid droplets for lung delivery can be produced by jet nebulisation,
vibrating mesh nebulisation, and colliding jets (Respimat® inhaler) [53],
which have been applied to aerosolising phages. Comparison between these
three methods showed differences in titre loss post-nebulisation [54]. Jet
nebulised active PEV44 phages was signi
icantly lower at
5.4
× 104 PFU/minute, compared to those aerosolised from a vibrating-mesh
nebuliser (3.3 × 108 PFU/minute) and soft-mist inhaler
(4.6 × 106 PFU/minute) [54]. The possible reason for such a discrepancy in
titre loss between the different nebulisers is likely due to the intense shearing
in jet nebulisers that damaged the phages [53, 54]. Infectivity correlates with
the structural integrity of phages as the extent of capsid and tail detachment
was associated with the titre loss of PEV44 [55]. The degree of reduction was
higher in Siphoviridae phages (e.g. D29) and Myoviridae (e.g. PEV44) [55] due
to their longer tails than those of Podoviridae phages [56]. The examination of
structural differences in the infectivity of nebulised phages revealed that the
long-tailed D29 and PEV40 suffered from more head-tail detachment that
correlated with the reduction in the titre [56]. On the other hand, jet
nebulisation had minimal impact on PEV2 as its short tail is less likely to
break. Therefore, structural differences between phages and the choice of the
nebuliser are important factors to consider for respiratory delivery.
FluMist® is the
irst intranasal vaccine against seasonal inluenza. It
contains the live attenuated in
luenza virus and is stable under refrigeration
[57]. The reason for its stability is due to having been frozen at a temperature
below the glass transition temperature [58]. Although phages are also viruses
and may also be formulated similarly, cold-chain maintenance is dificult and
costly. Therefore, it is worthwhile to investigate formulations that are stable
at room temperature, such as solid dosage forms.
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5.2 DryPowderA erosols
Dry powder formulations for inhalation are popular owing to their higher
chemical stability than liquids and storage at ambient temperature [59].
Lyophilisation has an immediate but minor negative impact on the infectivity
of speciic phages, depending on the excipients used [45, 60]. Storage of the
lyophilised formulation for another 27 months only showed an insigniicant
decrease in the titre [60]. Storage for 8 years at 4 °C did not reduce the titre
signiicantly (n = 1), except when 0.8 M trehalose was used as an excipient,
for which a 1.75-log titre reduction was observed [46]. However, lyophilised
powders have ill-deined particle shapes and sizes so they may not be
suitable for inhalation.
Spray drying is a one-step process that can produce inhalable phage
powders with only a moderate titre loss [47, 61, 62]. The spray drying
temperature may negatively impact phage stability, in turn affecting phage
infectivity and aerosol performance. A low drying temperature is required to
minimise this impact [63, 64]. The storage temperature may also inluence
phage viability [45, 62]. Storage of spray-dried phages PEV2 and PEV40 at 4
and 20 °C in vacuum packaging yielded different results that were
formulation-dependent [62]. For PEV2, formulations containing 70%
trehalose and 30% leucine were stable with no further titre reduction up to
1 year at both 4 and 20 °C. On the other hand, those containing 60% trehalose
and 40% leucine showed temperature-dependent titre reduction [62]. Similar
to the lyophilisation of phage ISP [60], spray drying PEV2 and PEV40 resulted
in an immediate reduction of 0.7 and 0.2 log PFU/mL, respectively, regardless
of the different excipient combinations [62]. PEV2 titres were not further
affected when stored at 4 and 20 °C if the formulation contained 70%
trehalose and 30% leucine [62]. However, when the trehalose content
decreased to 60%, PEV2 was stable when stored at 4 °C for up to 12 months
but its viability decreased signiicantly when stored at 20 °C after 6 months.
PEV40 displayed more variability in the titre and for all formulations and
temperatures studied but its titre was stable for up to 3 months with no
further degradation [62]. Currently, lactose is approved as an excipient for
inhalation. On the other hand, trehalose and leucine are yet to be approved
for inhalation, although they are Generally Recognised as Safe excipients for
other types of formulations. They have been used in experimental inhaled
powders as they can improve the physical stability of the drug/powder and
have relatively low toxicity [65]. Flexible small sugars such as trehalose
protects against heat and water-removal which are desirable traits for phage
formulations as the proteins require hydrogen bonds for structural stability
[66, 67] by decreasing molecular mobility [68]. Spray-dried phages PEV20
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and PEV61 showed different storage characteristics depending on the
formulation, which consisted of lactose (55–90%) and leucine (45–10%)
[47]. In vitro cell studies demonstrated that the combination of phage, lactose
and leucine did not negatively affect the viability of human epithelial cells and
macrophages, supporting the safety of these excipients [47]. A high lactose
content of 80% and above increased the stability of the phage powders at
ambient temperature when they were packed in an aluminium pouch at 15%
relative humidity (RH) and stored at 20 °C/60% RH [47]. This resulted in
minimal titre loss over 12 months for phages PEV1, PEV61 and PEV20. The
extent of titre reduction and the duration of stability during storage varied
between phage species. PEV20 was more prone to inactivation compared to
PEV1 and PEV61. A low leucine content (10%) was shown to be suficient to
protect phage powders from moisture-induced degradation. Another major
factor to consider is the difference between the glass transition temperature
(Tg) and storage temperature (Ts), i.e. Tg − Ts [68]. Higher storage RH lowers
the Tg, consequently lowering the Tg − Ts value, resulting in phage titre
reduction regardless of the storage temperature. Chang et al. [68]
demonstrated that the powder adsorbed more moisture at 33% RH than at
15% RH. Since water is a strong plasticiser, protein mobility was increased
and consequently phage stability decreased. The spray-dried phages
remained stable when Tg − Ts was >46 °C, hence it is vital to consider Tg when
selecting the storage conditions for phage powders. To facilitate storage,
phage powders should be stable at room temperature (20–25 °C), meaning
that Tg should be at least 71 °C, which may be achievable by choosing
excipient/s with a high Tg and/or keeping the storage RH low.
There is currently a lack of longer-term stability studies lasting 12 months
or longer, given that the shelf-life is very important if phage therapy is to be
extensively utilised in the future. The formulation of a personalised cocktail
from a phagogram in clinical settings will only be possible if there are viable
phage products readily available.
6 Future Dire ctions
Currently, there is no regulatory framework governing the manufacture and
use of phage products but Belgium has established a phage monograph for
magistral preparations endorsed by their Federal Agency for Medicines and
Health Products [69]. However, this is purposed for patient-speciic
compassionate use rather than scaled-up therapeutics such as antibiotics.
Phagoburn was the irst clinical trial of a GMP-grade phage cocktail and its
protocols were approved by the French Food Safety Agency [26]. Similar to
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biologics, phage manufacturers must be GMP compliant and require
regulations to ensure the safety, purity, and eficacy of the product. It is very
likely that the costs involved in the production of phage products will exceed
that of antibiotics, which would incur a inancial strain on the stakeholders.
However, given the increasing incidence of resistant infections, phage
therapy could be a potentially life-saving option, especially when used
concomitantly with antibiotics.
High-quality clinical trials of phage therapy are required. Due to the lack
of pharmacokinetic and pharmacodynamic studies, there is limited
understanding of the optimal dose of phages [6, 14]. Their dosage may be
species-speci
ic but the common dose tested in published studies is 107–
109 PFU/mL [6, 8, 9, 12, 20, 34, 70]. An in vivo study in neutropenic BALB/c
mice using an intratracheal anti-pseudomonas phage, PEV31, demonstrated
dose-dependent responses in phage replication in situ, the number of
emergent phage-resistant bacteria, and the level of proin
lammatory
cytokines (IL-1β, IL-6, TNF-α) [71]. However, the extent of bacterial load
clearance was independent of the dose of phage delivered [71]. It is unclear
whether this inding is phage-dependent or whether it is applicable to all
phages because there is insuficient data on dosing for all routes of phage
administration [14]. Nevertheless, there is an increasing number of
registered clinical trials on phages [72] that can mend the current gaps in
knowledge. A major safety concern of administering phages is their purity as
endotoxins released from the host bacteria as part of the manufacturing
process will negatively impact the patient. Furthermore, bacteriolysis by
phages during treatment may rapidly release endotoxins which may lead to a
cascade of pro-inlammatory responses. Although adverse events are seldom
reported in the literature and phage therapy is generally considered to be
safe [14], a systematic review reports that the quality of evidence on the
safety of phage therapy is low or moderate because most published studies
were case studies of individual patients [73]. FDA limits the endotoxin levels
for the single parenteral dose to 5 endotoxin units (EU)/kg of body weight
per hour of administration. Following current GMP is the safest method in
producing phages for clinical use, as conirmed by Fabijan et al. [70], who
reported no safety concerns in treating severe S.aureus infections.
Re-emergence of phage therapy for MDR infections has highlighted the
knowledge gaps that are preventing its wide clinical use. High-quality clinical
trials are undoubtedly needed to investigate their safety, quality, and eficacy.
Acknowledgement
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The authors received no inancial support for the research, authorship, and
publication of this article.
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