PolyTope® TATX-03 may help all of us to restore our lives: relief for the immunocompromised is coming
Dear reader: A warm welcome to our next blog.
Many people no longer wish to talk about COVID-19. Unfortunately, this understandable attitude does not reduce the risks of infection and consequent morbidity and mortality. Instead, we need sophisticated and smart interventions to protect ourselves against this persistent invader. Common interventions so far were wearing a facemask, social distancing, preventing spread of the virus by limiting travel and large gatherings, and through mass vaccination. However, some claim that these interventions are inconvenient and disrupt our social lives.
Mass vaccination and subsequent boosting have brought much relief but have not been the proverbially egg of Columbus. Why are we then not relieved from the virus as was expected by many experts? It is a simple question, but the answer is not simple at all. We give a few explanations, knowing that some are more complicated epidemiologically than described here.
For example, persons who are not vaccinated play a role in the preservation of the virus so long as this group is large enough. In addition, the world population is far from adequately vaccinated, which forms a dynamic reservoir for the virus to infect hosts and mutate, then posing a new threat to vaccinated people.
Another important explanation is that no vaccine ever was, currently is, nor ever will be 100% effective. One hundred percent efficacy means that all vaccinated persons acquire full immunity and do not fall ill when challenged. However, in the end, we are all unique and respond differently to vaccination. Recent research has indeed demonstrated that everyone has a unique immune profile which is as specific as a fingerprint1. The uniqueness of every creature is mother nature’s brilliant plan to give living species an opportunity to survive a threat by letting all individuals react differently on it.
In other words, the immune system of each person has a unique immune response when exposed to the same foreign substance, or invading micro-organism. This phenomenon explains why one person does not build up resistance, while another acquires full and active immunity. This means that even if all persons in a population are vaccinated, a certain percentage will remain unprotected or less protected. It must be noted here that many people are not able to acquire immunity at all given primary and secondary immunodeficiencies (on which we elaborate more below and in one of our next blogs).
A third explanation for the persistence of the virus is that an acquired immunity is, in most cases, not everlasting. Our body does this for a very good reason: it costs energy to maintain proteins active at a certain level and there are physical limits to the total solubility in, and to the osmolarity of, body fluids. It is normal for proteins to degrade, become inactive, and get cleared. And so, the anti-SARS-CoV-2 antibodies extinguish over time. The speed of this clearance is characterized by a biological half-life (the time required to decrease the concentration by half). The serum biological half-life of the predominant antibody, immunoglobulin G (IgG), is approximately 23 days. This would be the speed with which our first wall of defense against the coronavirus erodes if not boosted to restore full capacity. This may leave you confused; the interval between a last vaccination and a booster is longer than 23 days. This is because there is one other parameter which determines the endurance of a vaccination: the starting concentration of the protective antibodies.
Even though immunized people may still fall ill, the handcuffs of which we wrote in our former blog of March 31, 2022, do not fit anymore. In that case, the virus has sneakily changed its key antigen, the spike protein, so that antibodies produced in response to vaccination are not able to recognize the virus anymore and consequently are not capable of neutralizing this infectious agent.
Although there are more possible explanations, these are four important answers to the question: “why mass-vaccination did not eradicate SARS-CoV-2 so that we get our lives back?” They help us understand the risk of breakthroughs and why they happen. Vaccination with virus-specific antigens, an attenuated virus, or a virus vector, is not sufficient in preventing COVID-19. This is a disturbing message for large groups of us, the chronically ill and healthy alike. Ideally, visiting elderly, going to work, having medical surgery, or going to a sports event would not be hindered by this health-threatening infectious disease.
The immune-impaired persons among us have even more concerns and are affected disproportionally in their efforts to pick up their regular lives from before the pandemic. These patients are a continuously increasing heterogeneous group associated with congenital/genetic disorders, syndromes, malignancies, stem cell and organ transplantations, HIV et cetera. In addition, multiple comorbid conditions are associated with a higher risk and increased severity of infection as well. For example, the risk of a breakthrough infection with associated hospitalization and mortality is 485-fold higher in adult transplant patients compared with a healthy counter group2.
We should not fear a malicious virus that blows around causing breakthroughs and threatening continuously immune-impaired individuals. At ImmunoPrecise, we see it as our task to design, develop, and make available effective and safe pharmaceuticals. Currently, the medication from which a medical doctor can already choose to help people to protect themselves comprise viral inhibitors, immunomodulators and ready-to-use antibodies (immunotherapies).
The first group of medicines, the viral inhibitors, seems to be an attractive treatment. Some of them can be taken orally and should work as a prophylactic. However, for several viral inhibitors, the prevention of morbidity and mortality is not clear at all, and their risk-benefit is disputed. The WHO advises strongly against the use of some inhibitors, or otherwise recommend their conditional administration. In one instance, the FDA’s Antimicrobial Drugs Advisory Committee (AMDAC) raised concerns over the low effectiveness of a viral inhibitor. In addition, viral inhibitors are contraindicated in certain groups, such as pregnant and immunodeficient persons.
With respect to the immunomodulators, they influence the immune system’s response to a coronavirus infection. The rationale for their use stems from concerns of fatal ‘cytokine storms’ in the escalation of the disease. To reduce the elevated levels of inflammatory markers, one of the first immunomodulators used was dexamethasone which can be considered as an antique but effective drug. However, corticosteroids, like dexamethasone, are not particularly harmless; the list of adverse effects is long, and the incidence of them is high. In addition, they do not prevent infection. So, they are merely considered as a last resort when the prospects of the hospitalized patient are not favorable.
Therefore, a third group of medicines is attracting increasing attention to prevent and treat COVID19: immunotherapies. These include their use as vaccines as well, but they are passive immunizations exploiting ‘ready-to-use’ antibodies as in contrast to an active immunization involving the use of immunogen inducing, logically, an immune response. An important advantage of an immunotherapy is that upon administration, the tailor-made antibodies are available virtually immediately for action, whereas an active immunization needs at least seven days to obtain protective levels. A downside of immunotherapies is the high amount and volume that must be injected, which are easily more than one gram and ten milliliters, respectively. Therefore, this product is given intravenously over a longer time or subcutaneously through concurrent injections at different sites. Compare this amount and volume for a dose of e.g. Nuvaxovid (also sold as Novavax or Covovax) COVID-19 vaccine, which are 5 micrograms of protein and a half milliliter, respectively!
Of note here, the exploited antibodies should not accelerate the discussed inflammatory cascade. It is therefore that immunotherapies are indicated for treatment of COVID19 patients with mild-to-moderate symptoms, in addition to common prophylactic use. Several of these immunotherapies, consisting of one or two antibodies, have received conditional approval from the authorities for use in humans. However, the use of some of these preparations has been restricted in the meantime, as they were inactive against the Omicron variant of SARS-CoV-2.
ImmunoPrecise’s TATX-03 formulation consists of multiple antibodies which were selected in such a way that they are not only resilient towards (new emerging) variants-of-concern but also act synergistically. The synergistic action of TATX-03 may allow formulations with a much smaller dose compared to those of other immunotherapy producers. Therefore, we are most likely in better control of the starting dose and thus of the endurance of the treatment. We are very pleased that ImmunoPrecise is preparing various requests in different geographic regions for first use in humans so that PolyTope® TATX-03 can start to help us to restore our lives!
REFERENCES
1. Bondt A, Hoek M, Tamara S et al. (2021) Human plasma IgG1 repertoires are simple, unique, and dynamic, Cell Systems 12, 1131–43. Doi: 10.1016/j.cels.2021.08.008
2. Qin CX, Moore LW, Anjan S et al. (2021) Risk of Breakthrough SARS-CoV-2 Infections in Adult Transplant Recipients, Transplantation 105, e265-e266. Doi: 10.1097/TP.0000000000003907