Developments in Biologic and Inhaled Antifungal medications for ABPA
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ABPA (Allergic Bronchopulmonary Aspergillosis) is a serious allergic disease caused by a fungal infection of the airways. People with ABPA usually have severe asthma and frequent flare-ups that often require long-term use of oral steroids and antibiotics to treat secondary bacterial infections.
The two main treatments for ABPA are antifungal medication and oral steroids. Antifungal medication work by targeting the fungi causing the infection, limiting its growth and spread. This can help reduce the frequency of flare-ups and stabilize the condition but may also cause side effects such as nausea and, more rarely, liver damage. Oral steroids work by reducing inflammation and suppressing the immune system's response to the allergen, which can help control the symptoms of ABPA. However, long-term use can cause significant side effects, including weight gain, mood swings, and adrenal insufficiency.
These side effects can greatly impact quality of life, but both treatments may be necessary to prevent the disease from worsening. Therefore, new or improved treatments are needed.
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Fortunately, there have been recent developments in managing ABPA, and a review by Richard Moss (2023) highlights two promising types of treatment:
- Inhaled antifungal medication treat fungal lung infections by delivering the drug directly to the site of infection. This allows for a higher concentration of the drug to be delivered to the affected area while limiting the exposure of the rest of the body and therefore reduces side effects. For instance, inhaled itraconazole has been shown to reach concentrations high enough to kill or inhibit fungus growth. Further trials will be completed this year (2023) to assess its safety and effectiveness. Although still in development, these drugs offer hope for more effective and better-tolerated treatment options for patients with ABPA.
- Biologic medication is a completely new type of treatment that uses synthetic antibodies to target specific cells or proteins of our immune system instead of using a chemical compound. Omalizumab, a type of biologic, binds to immunoglobulin IgE and deactivates it. IgE is involved in the allergic response our bodies launch against foreign invaders and plays a big role in ABPA symptoms. Deactivation of IgE has been shown to reduce allergic symptoms. In clinical trials omalizumab has been shown to significantly (a) reduced the number of flare-ups compared to pre-treatment, (b) reduced the need for oral steroid use and lowered its necessary dose, (c) increased wean off steroids, (d) improved lung function and (e) improved asthma control. Additionally, other Monoclonal antibodies (Mabs) such as mepolizumab, benralizumab, and dupilumab have shown a reduction in flare-ups, total IgE and a steroid-sparing effect.
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According to Moss (2023), these new treatment approaches are highly effective in reducing hospital visits. Biologics seem highly effective, with up to a 90% reduction in flare-ups for ABPA patients and up to 98% efficacy in reducing the amount of oral steroid needed by the patient. If these new treatments continue to work well, it could potentially offer a new, higher quality of life for individuals with ABPA . Overall, these findings are promising, but further research is needed to confirm the effectiveness of these treatments specifically for ABPA.
Original paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9861760/
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Spring COVID Booster
COVID-19 levels of infection in the UK are far lower than they have been earlier in the pandemic, even while most people have returned to taking fewer precautions against infection. Increased immunity in the UK population caused by vaccination and infection has likely brought us to this better place.
However levels of immunity are not fixed and much like the common cold it gradually declines in each of us, leaving us open to re-infection within a year. Consequently, we must keep 'topping up' immunity in order to avoid severe symptoms should we be infected. For most of us that are now likely to be a natural process of periodic re-infection until the virus stops circulating so widely.
If you are in a highly vulnerable group it is safest to top-up your immunity without being infected by having a booster vaccination. The Uk government will launch a spring booster campaign shortly to address this need.
Those who will be offered this booster will only be the most at risk, so you may or may not be offered it depending on the opinion of your local hospital doctor or GP. The criteria for the spring booster seem to be more restricted than earlier boosters and will only be offered 6 months after your last booster.
Criteria for the spring campaign are:
- adults aged 75 years and over
- residents in a care home for older adults
- individuals aged 5 years and over who are immunosuppressed (Your doctor will get guidelines to decide this for you)
There will likely be a less restricted booster jab in autumn 2023 too.
Drug Induced Photosensitivity
What is drug-induced photosensitivity?
Photosensitivity is the abnormal or heightened reaction of the skin when exposed to ultraviolet (UV) radiation from the sun. This leads to skin that has been exposed to the sun without protection becoming burnt, and in turn, this can increase the risk of developing skin cancer.
There are several medical conditions like lupus, psoriasis and rosacea that can increase a person's sensitivity to ultraviolet light. A more comprehensive list of known conditions can be found here.
Drug-induced photosensitivity is the most common type of skin-related adverse drug reaction and can occur as a result of topical and oral medications. Reactions happen when a component of the medication combines with UV radiation during sun exposure, causing a phototoxic reaction that appears as severe sunburn, identified by swelling, itchiness, profuse redness and in the worst cases, blistering and oozing.
Patients taking antifungal medications, in particular, Voriconazole and Itraconazole (the former being more widely known for causing reactions), are often aware of the increased risks of photosensitivity; however, these are not the only drugs that can induce an abnormal response to UV exposure. Other drugs that have been reported to cause photosensitivity are:
- NSAIDs (Ibuprofen (oral and topical), naproxen, aspirin)
- Cardiovascular medication (furosemide, ramipril, amlodipine, nifedipine, amiodarone, clopidogrel – just a few)
- Statins (simvastatin)
- Psychotropic drugs (olanzapine, clozapine, fluoxetine, citalopram, sertraline – just a few)
- Antibacterial medications (ciprofloxacin, tetracycline, doxycycline)
It is essential to note that the above list is not exhaustive, and reported reactions range from rare to frequent. If you think a medication other than your antifungal is causing a reaction to the sun, speak to your pharmacist or GP.
How to protect yourself
In most cases, patients can't stop taking the medication that can predispose them to photosensitivity. Staying out of the sun isn't always possible either - quality of life is always an important consideration; therefore, extra care should be taken to protect their skin while outside.
There are two types of protection:
- Chemical
- Physical
Chemical protection is in the form of sunscreen and sunblock. However, it is important to remember that sunscreen and sunblock are not the same. Sunscreen is the most common type of sun protection, and it works by filtering the sun's UV rays, but some still get through. Sunblock reflects the rays away from the skin and prevents them from penetrating it. When buying sunscreen, look for a sun protection factor (SPF) of 30 or above to protect against UVB and at least a UVA protection rating of 4 stars.
Physical protection
- NHS guidance advises staying in the shade when the sun is strongest, which in the UK is between 11am and 3pm from March to October
- Use a sunshade or umbrella
- A wide-brimmed hat that shades the face, neck and ears
- Long-sleeved tops, trousers and skirts made of close-weave fabrics that stop sunlight from penetrating
- Sunglasses with wraparound lenses and wide arms that conform to the British Standard
- UV protective clothing
Links to further information
NAC Physio Mairead runs the Manchester Marathon for the Fungal Infection Trust
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Adrenal insufficiency
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Cortisol and aldosterone are important hormones our bodies need in order to stay healthy, fit and active. They are produced by the adrenal glands which are sited at the top of each of our kidneys. Sometimes our adrenal glands may not be able to produce enough cortisol and aldosterone, for example when the glands are mistakenly attacked and destroyed by a person’s immune system – this is Addison’s disease (see also addisonsdisease.org.uk). The lost hormones can be replaced by medication from an endocrinologist and the patient can live a normal life. This form of adrenal insufficiency is not a feature of aspergillosis.
Unfortunately, people who take corticosteroid medication (e.g. prednisolone) for longer periods of time (more than 2-3 weeks) can also find that they have low levels of cortisol as their corticosteroid medication can suppress the production of their own cortisol, especially if high doses are taken.
Once the corticosteroid medication is stopped your adrenal glands will usually re-activate but it may take some time which is why your doctor will tell you to slowly taper down your dose of corticosteroid carefully over several weeks, to allow your adrenal glands to recover.
What has this got to do with aspergillosis?
People with chronic forms of aspergillosis & asthma can find themselves taking corticosteroid medication for quite long periods of time in order to control their breathlessness and allow comfortable breathing. Consequently, they may find that they have to take care when reducing their dose of corticosteroid and proceed gradually to allow their own natural cortisol production to resume safely. Reducing too quickly can cause a range of symptoms including fatigue, fainting, nausea, fever, dizziness.
These are powerful drugs and must be handled with care so if you have any concerns contact your GP without delay.
Other medication you may be taking to treat aspergillosis has also rarely been associated with causing adrenal insufficiency e.g. some azole antifungal medication, so it is worthwhile to remain vigilant for relevant symptoms (see list above). However, note that symptoms such as fatigue are very common in someone with aspergillosis.
For other details on taking corticosteroid medication see the steroids page
Steroid Emergency Card
The NHS has issued a recommendation that all patients who are steroid dependant (i.e. should not abruptly stop corticosteroid medication) carry a Steroid Emergency Card to inform health practitioners that you need daily steroid medication in the event you are taken into hospital and are unable to communicate.
Information on obtaining a card can be found here.
NOTE patients attending the National Aspergillosis Centre in Manchester can collect a card at pharmacy
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Vaccine Types
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Vaccines. Something most, if not all of us, are familiar with. MMR (Measles, Mumps & Rubella), TB (Tuberculosis), Smallpox, Chicken Pox, and the more recent HPV (Human Papillomavirus) and Covid-19 vaccines are just a few of the many available to protect us from harmful pathogens (an organism that causes disease like bacteria or viruses – aka 'germs'). But what exactly is a vaccine, and how does it protect us?
Firstly, to understand vaccines, it helps to have a fundamental understanding of the immune system. The immune system is the body's natural defence against harmful pathogens. It is a complex system of organs and cells that work together to help fight off infection caused by invading pathogens. When a 'germ' enters our body, the immune system triggers a series of responses to identify and destroy it.
Outward signs we are having an immune response are:
- A raised temperature (fever) and uncontrollable shivering (Rigors).
- Inflammation; this can be internal or visible on the skin's surface – for example, from a cut.
- Coughing & Sneezing (mucus traps germs, which are then removed by the action of coughing or sneezing).
Types of immunity:
Innate (also called nonspecific or natural) immunity: We are born with a combination of physical (skin and mucous membranes in the respiratory and gastrointestinal tracts), chemical (for example, stomach acid, mucous, saliva and tears contain enzymes that breakdown the cell wall of many bacteria1), and cellular (natural killer cells, macrophages, eosinophils are just a few2) defences against pathogens. Innate immunity is a type of general protection designed to immediately respond to the presence of a pathogen.
Adaptive immunity: The adaptive, or acquired, immune response is more specific to an invading pathogen and occurs after exposure to an antigen (a toxin or foreign substance which induces an immune response) either from a pathogen or vaccination.3
Below is an excellent video from TedEd that provides a simple yet detailed explanation of how the immune system works.
Types of vaccines
There are several different types of vaccines that use various mechanisms to 'teach' our immune systems how to fight off specific pathogens. These are:
Inactivated vaccines
Inactivated vaccines use a version of the pathogen that has been killed. These vaccines generally require several doses or boosters for immunity to be ongoing. Examples include Flu, Hepatitis A and Polio.
Live-attenuated vaccines
A live-attenuated vaccine uses a weakened live version of the pathogen, mimicking natural infection without causing serious disease. Examples include Measles, Mumps, Rubella, and Chickenpox.
Messenger RNA (mRNA) vaccines
An mRNA vaccine contains no actual part of the pathogen (alive or dead). This new type of vaccine works by teaching our cells how to make a protein that will in turn, trigger an immune response. In the context of Covid-19 (the only mRNA vaccine approved for use in the form of the Pfizer and Moderna vaccinations), the vaccine instructs our cells in making a protein found on the surface of the Covid-19 virus (the spike protein). This causes our bodies to create antibodies. After delivering the instructions, the mRNA is immediately broken down.4
Subunit, recombinant, polysaccharide, and conjugate vaccines
Subunit, recombinant, polysaccharide, and conjugate vaccines do not contain any whole bacteria or viruses. These vaccines use a piece from the pathogen's surface —like its protein, to elicit a focused immune response. Examples include Hib (Haemophilus influenzae type b), Hepatitis B, HPV (Human papillomavirus), Whooping cough (part of the DTaP combined vaccine), Pneumococcal and Meningococcal disease.5
Toxoid vaccines
Toxoid vaccines are used to protect against pathogens that cause the release of toxins. In these cases, it is the toxins that we need to be protected from. Toxoid vaccines use an inactivated (dead) version of the toxin produced by the pathogen to trigger an immune response. Examples include Tetanus and Diphtheria.6
Viral Vector
A viral vector vaccine uses a modified version of a different virus (the vector) to deliver information in the form of a genetic code from a pathogen to our cells. In the case of the AstraZeneca and Janssen/Johnson & Johnson vaccines and Covid-19, for example, this code teaches the body to make copies of the spike proteins – so if exposure to the actual virus occurs, the body will recognise it and know how to fight it off.7
The video below was developed by Typhoidland and The Vaccine Knowledge Project and describes what happens inside our cells when we are infected with a virus - using Covid-19 as the example.
References
- Science Learning Hub. (2010). The body's first line of defence. Available: https://www.sciencelearn.org.nz/resources/177-the-body-s-first-line-of-defence Last accessed 18 Nov 2021.
- Khan Academy. (Unknown). Innate Immunity. Available: https://www.khanacademy.org/test-prep/mcat/organ-systems/the-immune-system/a/innate-immunity Last accessed 18 Nov 2021.
- Molnar, C., & Gair, J. (2015). Concepts of Biology – 1st Canadian Edition. BCcampus. Retrieved from https://opentextbc.ca/biology/
- Mayo Clinic Staff. (Nov 2021). Different types of COVID-19 vaccines: How they work. Available: https://www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/different-types-of-covid-19-vaccines/art-20506465 Last accessed 19 Nov 2021.
- Office of Infectious Disease and HIV/AIDS Policy (OIDP). (2021). Vaccine Types. Available: https://www.hhs.gov/immunization/basics/types/index.html Last accessed 16 Nov 2021.
- Vaccine Knowledge Project. (2021). Types of vaccine. Available: https://vk.ovg.ox.ac.uk/vk/types-of-vaccine Last accessed 17 Nov 2021.
- CDC. (Oct 2021). Understanding Viral Vector COVID-19 Vaccines. Available: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/viralvector.html#:~:text=First%2C%20COVID%2D19%20viral%20vector,is%20called%20a%20spike%20protein Last accessed 19 Nov 2021.
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Antifungal Drug Pipeline
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Many of our patients already know of the increasing need for new antifungal drugs; treatments for fungal diseases like aspergillosis have significant limitations. Toxicities, drug-drug interactions, resistance, and dosing are all issues that can complicate therapy; therefore, the more treatment options we have, the more likely we are to find an optimal therapeutic option for patients.
Developing antifungal drugs is difficult because of the biological similarities between people and fungi; we share many of the same biological pathways as fungi, creating issues in developing safe antifungals. To develop new antifungal drugs, researchers must look at how they can exploit some of the differences we do have.
Below is a layman’s breakdown of a recently published review that looked at seven antifungal drugs currently in various stages of development. The majority of new antifungals have been new versions of old drugs, but the ones discussed in this review have new mechanisms of action and different dosing regimens, so, if approved, these drugs could provide a ray of hope in the not so distant future in terms of treatment.
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Rezafungin
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Rezafungin is currently in phase 3 of development. It is a member of the echinocandin class of drugs, including micafungin and caspofungin; Echinocandins work by inhibiting a fungal cell wall component essential to homeostasis.
Rezafungin has been developed to retain the safety benefits of its echinocandin predecessors; while enhancing its pharmacokinetic and pharmacodynamic properties to create a unique, longer-acting, more stable treatment that allows for weekly intravenous rather than daily administration, potentially expanding treatment options in the setting of echinocandin resistance.
Fosmanogepix
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Fosmanogepix is known as a first-in-class drug (so first of its kind antifungal) that blocks the production of an essential compound that is important for the construction of the cell wall and self-regulation. Blocking the production of this compound weakens the cell’s wall enough that the cell can no longer infect other cells or evade the immune system. It is currently in Phase 2 clinical trials and is showing promising results in the oral and intravenous treatment of multiple invasive fungal infections, demonstrating efficacy in multi-drug resistant and other difficult-to-treat infections.
Olorifim
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Olorifim falls under an entirely new class of antifungal drugs called orotomides. The orotomides have a distinct mechanism of action, selectively targeting a key enzyme in pyrimidine biosynthesis. Pyrimidine is an essential molecule in DNA, RNA, cell wall and phospholipid synthesis, cell regulation, and protein production, so when Olorofim targets this enzyme, it profoundly affects the fungi. Unfortunately, Olorifim isn’t broad spectrum, and it only kills a few fungi – pertinently, Aspergillus, and the fungus that causes valley fever (which affects the brain), Coccidioides. Since its discovery, it has progressed through pre-clinical studies and phase 1 human trials and is currently an ongoing phase 2 clinical trial testing its use orally and intravenously.
Ibrexafungerp
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Ibrexafungerp is the first of a new class of antifungals called Triterpenoids. Ibrexafungerp targets the same essential component of the fungal cell wall that the echinocandins do, but it has an entirely different structure, making it stabler and meaning it can be given orally; differentiating Ibrexafungerp from the three currently available echinocandins (caspofungin, micafungin, andulafungin), which can only be given intravenously limiting their use to hospitalised patients and those with indwelling venous access.
There are two ongoing phase 3 trials of ibrexafungerp. The most extensive enrolling study to date is the FURI study, which evaluates the efficacy and safety of Ibrexafungerp among patients with severe fungal infection and who are unresponsive or intolerant of standard antifungal agents. The oral formulation was recently approved by the USA’s Food and Drug Administration (FDA) for the treatment of vulvovaginal candidiasis (VVC).
Oteseconazole
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Oteseconazole is the first of several tetrazole agents designed with the goal of greater selectivity, fewer side effects, and improved efficacy compared to currently available azoles. Oteseconazole has been designed to tightly bind to an enzyme called cytochrome P450. When we discussed earlier fungi and humans being similar, cytochrome P450 is one of those similarities. Human cells contain various species of cytochrome P450, which are responsible for many important metabolic functions. Therefore, if azole antifungal agents inhibit the human cytochrome P450, the result can be adverse reactions. But, unlike other azole antifungals, Oteseconazole only inhibits the fungal cytochrome p450- not the human one because of its affinity for the target enzyme (cytochrome P450) is greater. This should mean fewer drug-drug interactions and less direct toxicity.
Oteseconazole is in phase 3 of development and is currently under FDA consideration for approval to treat recurrent vulvovaginal candidiasis.
Encochleated Amphotericin B
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Many of our patients will already be aware of Amphotericin B, which has been around since the 1950s. Amphotericin B falls under the class of drugs called Polyenes- the oldest class of antifungal drugs available. They kill fungi by binding to ergosterol which acts to maintain cell membrane integrity. The drug works by stripping away the ergosterol, causing holes in the cell membrane, making it leaky enough to fail. But, polyenes also interact with cholesterol in human cell membranes, meaning they have significant toxicities. Encochleated Amphotericin B has been developed to avoid these significant toxicities – its novel lipid nanocrystal design allows for drug delivery directly to the infected tissues, shielding the body from unnecessary exposure – and it can be given orally, potentially reducing hospital stays.
Encochleated Amphotericin B is currently in phases 1 & 2 of development, so a little way off. Still, it promises the potential of an oral drug with little, if any, of the typical toxicities of amphotericin B.
ATI-2307
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ATI-2307 is in the very early stages of development and is a new antifungal drug with a unique mechanism of action. ATI-2307 inhibits mitochondrial function (mitochondria are structures within cells that convert food to energy), decreasing the production of ATP (adenosine triphosphate), which is the molecule that carries energy, leading to growth inhibition.
As mentioned earlier, ATI-2307 is still in the early stages. Still, researchers have completed three Phase 1 clinical studies that demonstrated it was well tolerated in humans at anticipated therapeutic dose levels. Thus, the clinical role for ATI–2307 is unclear; however, its broad in vitro activity against a host of important fungal pathogens, including multi-drug resistant organisms, could translate into a critical role for this compound, especially for fungal infections due to drug-resistant organisms such as azole-resistant Aspergillus species.
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Therapeutic drug monitoring (TDM)
[et_pb_section fb_built="1" admin_label="section" _builder_version="4.16" global_colors_info="{}" theme_builder_area="post_content"][et_pb_row admin_label="row" _builder_version="4.16" background_size="initial" background_position="top_left" background_repeat="repeat" global_colors_info="{}" theme_builder_area="post_content" custom_margin="7px|auto|7px|auto|true|false"][et_pb_column type="4_4" _builder_version="4.16" custom_padding="|||" global_colors_info="{}" custom_padding__hover="|||" theme_builder_area="post_content"][et_pb_text admin_label="Text" _builder_version="4.16" background_size="initial" background_position="top_left" background_repeat="repeat" global_colors_info="{}" theme_builder_area="post_content"]Therapeutic drug monitoring (TDM) is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication levels in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed.
When prescribing and managing oral antifungal medication, each needs to be carefully managed for each patient - the table below gives some standard guidelines as used at the UK National Aspergillosis Centre by its specialist pharmacists.
When will there be a vaccine for aspergillosis?
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[et_pb_column type="4_4"][et_pb_text admin_label="Text"]Why are there no vaccines for fungal infections?
Unfortunately, our understanding of immunity to fungi lags far behind our understanding of bacterial or viral infections. There are currently no vaccines available for any fungal infection, but several groups around the world are working towards designing and getting them approved for use in clinics.
The fungal vaccine currently nearest to the finish line is called NDV-3A. It is designed to boost immunity against Candida and prevent vaginal thrush (yeast infection), which will be of great comfort to people suffering from recurrent thrush (4+ infections per year).
Current efforts to produce an Aspergillus vaccine are mainly aimed at preventing invasive aspergillosis, which kills around 200,000 people per year worldwide. Many of these infections could be prevented if we had a way to vaccinate high-risk patients before starting medical treatments that lower their immunity (for example chemotherapy, transplants, strong steroids). However, it is very difficult for a person who already has an existing immunodeficiency to mount an effective immune response.
Efforts are also being made to develop a 'pan-fungal' vaccine, which would protect against many fungal pathogens at once.
What aspergillosis vaccines are in the pipeline?
Several approaches to designing an Aspergillus vaccine have been tried and are starting to achieve promising results in mice. Some researchers have tried injecting purified (recombinant) single proteins, while others have tried using complex mixtures made by fragmenting Aspergillus cell wall matter.
Earlier this year, staff at the Center for Vaccines and Immunology (University of Georgia, USA) tried using a recombinant protein called AF.KEX1, which is naturally found on the surface of Aspergillus cells. Vaccinated mice showed a good antibody response and grew smaller amounts of Aspergillus in their lungs. Importantly, they were less likely to die even if their immune systems were suppressed using corticosteroids.
- Read the research paper: Rayens et al (2021)
- Read an in-depth article about Aspergillus vaccines development: Levitz (2017)
• Read about how the same group used their microbiology skills to help during the COVID-19 pandemic
Will they be used to prevent CPA / ABPA in future?
Even after a vaccine for invasive aspergillosis has been approved, more work will be needed to find out whether it is also effective in preventing CPA and/or ABPA. It is much harder to predict who is at risk of developing chronic forms of aspergillosis because they are so rare even among people who have a known risk factor – most people with COPD do not develop CPA, and most people with asthma do not develop ABPA. This make it very hard to decide who should be vaccinated. It also makes it difficult to recruit enough of the right patients to run a meaningful clinical trial.
So how long?
As with many medical conditions, a prevention is better than a cure. But this is a long-term goal and it is impossible to predict with any accuracy when an Aspergillus vaccine will be available to patients.
We might hope to see some early-stage trials in humans in the next 3-5 years, but there is no guarantee that any of the current candidates will be effective or safe enough in humans to justify larger trials or be rolled out in clinics.
On the other hand, the COVID-19 pandemic has generated an enormous amount of public interest and new technologies for vaccination. Multiple COVID-19 vaccines were developed and brought to the public on a timescale that could scarcely be imagined even just 5 years ago. We may find that the vaccine development landscape changes beyond recognition in the near future and brings the prospect of an Aspergillus vaccine closer than we thought.
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