Understanding the allergic response
What is an allergy?
Allergies occur when a person’s immune system mistakes an allergen, such as pollen, as something dangerous.
In response, the body produces an antibody called IgE that recognizes a particular part of the allergen.
IgE then quickly attaches to specialized immune cells, called mast cells. When the allergic person encounters the allergen, IgE will signal to the mast cells to release chemicals, causing a reaction, such as itching and redness. This process can occur within minutes after being exposed to the allergen.
Typically, allergies are diagnosed using a skin prick test, in which an allergist exposes a patient’s skin to suspected allergens. If the patient is allergic to one of the substances, they will develop a localized allergic reaction of redness and itchiness in the skin.
However, the test results are hard to read in some patients, such as in those with underlying skin conditions. From the 1920s-1970s, an alternative test, called the Prausnitz–Küstner (P-K) test, was used for these patients. In the P-K test, an allergist would take a patient's blood serum, which contains IgE antibodies, and transfer it to a non-allergic volunteer's skin. The allergist would then test various suspected allergens on the skin of the volunteer. If the patient is allergic, the transferred IgE antibodies would respond, resulting in a localized allergic reaction. Importantly, the P-K test was safe and demonstrated that the transfer of IgE was temporary and remained local, meaning there was no risk of developing an active allergy or a systemic reaction in the healthy volunteer.
At Tochikunda, we realized that we could utilise the human body’s natural allergic response to safely diagnose infections or cancer.
Our diagnostic will consist of a topical cream, injection or small minimally-invasive implant, similar to the standard contraceptive implant, that releases an antibody, called IgE, which recognizes a pathogen or cancer biomarker. The diagnostic may be applied to epithelial or mucosal tissues, such as the gums.
These antibodies prime specialized immune cells, called mast cells, to release chemicals upon encounter with the pathogen or cancer biomarker, causing a mild and localized reaction of itching and redness identical to the reaction produced in the Prausnitz–Küstner (P-K) test.
If the person becomes infected, IgE will recognize the virus and signal the mast cells to release chemicals, causing a mild, local allergy-like reaction.
This will notify the person to immediately self-isolate or seek appropriate treatment before they infect others.
To stop the local allergic reaction, the person can take over-the-counter allergy medications and have the diagnostic removed if it is an implant.
CONTINUOUS: Unlike other diagnostics, our device provides continuous monitoring, allowing for early diagnosis.
SAFE: The concept of our diagnostic device is based on the P-K test, which demonstrates that the passive transfer of IgE results in a temporary and localized reaction without the risk of developing an active allergy or a systemic reaction. In our device, the IgE antibodies will not extend past the application site.
SPECIFIC: Allergies are prevalent, meaning many people have sensitized mast cells. Without the allergen, people do not exhibit symptoms. Our diagnostic will only provide a localized allergic reaction when the pathogen or cancer biomarker is present.
TEMPORARY: When attached to mast cells, IgE only lasts in the body for a few weeks. Upon removing our device or ceasing use of our injection or topical cream, the IgE antibodies will leave the body, and you will not develop a permanent allergy.
EASY TO USE: Our device will last for months at a time with an obvious reaction if there is an infection or cancer, removing the need to frequently visit the doctor or testing centre.
It has been estimated that up to 62% of new infections are spread from people who have not yet developed disease symptoms, making this a ‘silent infection’. To eliminate this virus, a highly effective means of quickly identifying asymptomatic and presymptomatic infections is required. Our product will detect infection early, allowing infected people to immediately take action to prevent spreading the virus to others, with the goal of eliminating the coronavirus.
Our diagnostic is complementary to vaccines. Vaccines are not 100% effective, meaning that some vaccinated people may still get sick with COVID-19 and may be infectious. In addition, it is possible that some patients for whom the vaccine prevents severe illness with COVID-19 may still spread the virus. Detecting the virus early is necessary to prevent transmission to those not vaccinated or those who did not build up an effective immunity.
Due to the lack of an effective vaccine, highly effective testing for HIV is critical for prevention and elimination. Worldwide, 25% of people infected with HIV are unaware that they have the virus. Some of these patients are in the highly infectious presymptomatic stage, which helps drive the pandemic.
Early therapy is beneficial for the patient’s health and the general population as it reduces the onward transmission of HIV by as much as 89%. Importantly, Post Exposure Prophylaxis (PEP) can prevent HIV infection, but only if taken within 72 hours of HIV exposure. Our product will detect HIV infection early, possibly within the timeframe for PEP.
Early diagnosis can lead to better clinical outcomes for patients. Our product will detect some cancer biomarker molecules and enable early diagnosis of some cancers.
The COVID-19 pandemic has shown us how crucial it is to stay on top of emerging infections. Our products can be rapidly adapted to detect emerging infections, potentially saving millions of lives in future disease outbreaks.
Will IgE antibodies against the coronavirus cause antibody-dependent enhancement (ADE)?
ADE occurs when an antibody binds to a virus and enhances its entry into human cells, exacerbating COVID-19 severity. Thankfully, this phenomenon will not happen with IgE antibodies, as ADE is primarily mediated by a different type of antibody, called IgG (Kulkarni R 2019). In addition, although ADE can occur in coronaviruses, it is promoted by antibodies to the spike (S) protein on the viral membrane, which facilitates entry into host cells. In this case, antibodies bind to the S protein, enhancing phagocytosis and infection of immune cells, such as macrophages (Yang ZY 2005, Vennema H 1990, Lee WS 2020). To eliminate the risk of ADE and enhanced infection of mast cells in our diagnostic, we use antibodies targeting an internal protein, called the nucleocapsid (N), which has no risk of ADE (Buchholz UJ 2004).
Is there a risk of anaphylaxis/anaphylactic shock?
Anaphylaxis is a rapid-onset allergic reaction that occurs systemically. It usually results when an allergen is introduced into the bloodstream (such as insect venom) or the gut (such as peanuts), resulting in the spread of the allergen via the bloodstream and activation of mast cells associated with blood vessels throughout the entire body (Murphy K 2012). In our diagnostic, IgE will be introduced locally and will only sensitise mast cells in that tissue. In the Prausnitz-Kustner (P-K) test, in which IgE is administered to the skin, recipients develop a local swelling and redness reaction without risk of systemic reactions (Feinberg SM 1934, Cohen SG 2004), supporting the safety of our diagnostic.
On the P-K test: “It should be remembered that the main objection to the routine use of intracutaneous direct testing – that is, the danger of systemic reaction – does not apply here.”
–Feinberg Samuel M, M.D., Allergy in General Practice, 1934.
Murphy, Kenneth et al., Janeway's Immunobiology. 8th ed. New York: Garland Science, 2012.
Is there a risk of permanent allergic sensitization?
We do not believe there is a risk of permanent allergic sensitization to the pathogen or cancer antigen detected by our diagnostic. Our diagnostic is based on the P-K test, which only resulted in a local and temporary passive sensitization of P-K test subjects , (Vaughan WT 1931, Cohen SG 2004). Users of our diagnostic will take allergy medications following a reaction so that it quickly resolves, like in the P-K test. IgE from our diagnostic will have a half-life of a few weeks in the body and B cells will not start making IgE so there will not be a permanent sensitization. We will confirm that our product does not cause permanent sensitization in preclinical and clinical trials.
On the P-K test: “We can withdraw some blood from the arm vein of the patient and inject minute amounts of the serum obtained therefrom into the skin of another normal person. This second person’s skin becomes passively sensitized at the sites of inoculation to the same allergens. We say passively sensitized, because it is only at the sites of inoculation that the sensitization is carried over. The blood does not become sensitized. The second person does not become allergic. Even the local sensitization passes away after a short time, and he is not at all the worse for the experience. He has been passively, not actively sensitized.”
– Vaughan Warren T, M.D., Allergy and Applied Immunology, 1931.
Will the topical cream or implant be effective at delivering antibodies?
Topical administration of therapeutic antibodies on the skin, eye, and vagina have been described for multiple diseases in human and animal models (Jones RG 2016, Morris GC 2014). Importantly, the topical application of monoclonal antibodies in the mouth showed high absorption levels in the gums in a mouse model (Balsari A 2001), demonstrating the plausibility of our diagnostic device for SARS-CoV-2 diagnosis. In addition, antibodies applied topically to the skin of mice did not enter the blood or other organs (Kopecki Z 2013), further supporting our product’s safety. Controlled release of antibodies via implants has also been developed and validated in mouse models (Lathuilière A 2016, Vernon RB 2018).
Jones RG, Martino A., Crit Rev Biotechnol. 2016;36(3):506-20.
Balsari A et al., Br J Cancer. 2001;85(12):1964-1967.
Kopecki Z et al., J Invest Dermatol. 2013 Apr;133(4):1008-16.
Morris GC et al., PLoS One. 2014 Dec 29;9(12):e116153.
Lathuilière A et al., Brain. 2016 May;139(Pt 5):1587-604.
Vernon RB et al., Mater Sci Eng C Mater Biol Appl. 2018 Dec 1;93:390-398.
Is the COVID-19 diagnostic still necessary now there are effective vaccines?
COVID-19 diagnostics are still necessary following the development of vaccines. Vaccines are not 100% effective, meaning that some vaccinated people may still get sick with COVID-19. Furthermore, effective vaccines may prevent severe illness but may not prevent shedding of the virus (Suess T 2012). Therefore, a vaccinated individual can become infected with the coronavirus and not develop symptoms because of the vaccine; however, they may still have enough virus to transmit to others. Our diagnostic will be complementary to vaccines, especially in those at high risk of infection, such as health-care workers.
In addition, we believe our diagnostic will enable the elimination of the coronavirus and HIV by detecting infections early before they spread.
Suess T. et al., PLoS One. 2012;7(12):e51653.
How will your diagnostic enable the elimination of the coronavirus and HIV?
Like others (Baker MG et al. BMJ 2020), we believe elimination could be the optimal strategy for dealing with the coronavirus and other emerging diseases. The criteria for the possibility of eliminating a disease are (CDC MMWR Suppl 1999):
Simple and effective diagnosis before onward transmission. We believe that our diagnostic will satisfy this criterion.
Effective intervention. Highly effective vaccines have been developed for COVID-19 though their impact on transmission is currently unknown, and there are highly effective treatments for HIV that also prevent HIV transmission (Hull MW, Montaner JS, J Food Drug Anal. 2013).
Countries like New Zealand have proven the principle of COVID-19 elimination (Baker MG et al. BMJ 2020). We hope that our diagnostic will enable elimination in more countries, and ultimately the whole world.
Centers for Disease Control and Prevention (CDC). Global disease elimination and eradication as public health strategies. Proceedings of a conference. Atlanta, Georgia, USA. 23-25 February 1998.MMWR Suppl 1999;48:1-208.pmid:11186140
Baker Michael G, Wilson Nick, Blakely Tony. Elimination could be the optimal response strategy for covid-19 and other emerging pandemic diseases BMJ 2020; 371 :m4907
Hull MW, Montaner JS. HIV treatment as prevention: the key to an AIDS-free generation. J Food Drug Anal. 2013;21(4):S95-S101. doi:10.1016/j.jfda.2013.09.043
Why is the P-K test no longer used?
The P-K test was used to diagnose allergy for patients in which direct skin testing was not feasible from the early 1920s until the 1970s. However, in the P-K test, the blood serum of one patient is transferred to another individual, which raised concerns about infecting the recipient with blood-borne pathogens, such as hepatitis and HIV (Cohen SG 2004). This is not a concern for our diagnostic as it only contains recombinant IgE, and there is no blood serum transfer.