The SARS-CoV-2 variant Omicron is causing the currently sky-rocketing incidences of COVID-19 infections. Peptide-based T cell targeting vaccines might be a way out of the ongoing pandemic.
A blog by Dr. Nadja Berger //
Who thought that we end up in such a long-lasting pandemic in 2022, with still no end in sight after about two years? When I think back to the beginning of 2020, I remember hearing about an outbreak of a novel virus in China. It felt so far away, and I didn’t expect any impact on my own life. Moreover, I certainly didn’t expect to witness a lockdown just a couple of weeks later, right here in Germany, because of this virus.
What exactly happened? How did we end up in a global crisis because of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19)? This blog post will guide you through the most relevant developments and provide a cautious assessment of dealing with these and upcoming threats.
The first coronavirus was isolated from a chicken embryo almost a century ago, in 1937, while the first human coronavirus (hCoV) 229E was discovered some decades later, in 1965. This virus family received its name from the characteristic spikes on its surface, which have a crown-like appearance and reminded the discoverer of the sun’s corona. Today, seven types of human coronaviruses are known (Link). Still, only some are pathogenic, and they did not appear before the 21st century. The three most fatal human coronaviruses are SARS-CoV (severe acute respiratory syndrome coronavirus 1), MERS-CoV (middle east respiratory syndrome-related coronavirus), and SARS-CoV-2. SARS emerged in 2002/2003 and MERS in 2012. However, although they caused devastating pandemics, none of them led to such a dramatic global event as SARS-CoV-2 did.
of relevant coronaviruses.
What are the critical differences between SARS-CoV-2 and previous coronaviruses, especially SARS and MERS, that allowed only SARS-CoV-2 to spread worldwide in the way it did? Indeed, the answer is multifaceted. Let’s look at these three coronaviruses to see what we can learn.
All three coronaviruses – SARS, MERS, and SARS-CoV-2 – are of zoonotic origin, most likely first hosted in bats. However, they presumably have different intermediate reservoirs before being transmitted to humans. Viral transmission of MERS occurs through camels. The two SARS viruses were most likely transmitted to humans on wet animal markets from live wild animals. Thus, stopping the spread of SARS by wet animal markets regulation should be feasible for the animal-to-human pathway. In the case of MERS, it is not that easy since the animal owners need to keep in contact with their camels. Therefore, it is not surprising that MERS is still circulating, and regional outbreaks are recurring from time to time (Link).
The first SARS-CoV outbreak was traced back to a market in Foshan in the southeast of China. In contrast, the first identified MERS-CoV case is rooted in Saudi Arabia. SARS-CoV-2 began spreading in Wuhan, central China, during the busy Chinese (Lunar) New Year. The outbreak location might explain the rapid spread, as “Wuhan is the major air and train transportation hub of central China” (Link). Consequently, the virus rapidly spread across China and globally through human-to-human transmission.
Two more factors accelerated the dissemination of SARS-CoV-2. First, the many asymptomatic cases of SARS-CoV-2 infection allow unnoticed virus transmission, and second, infected persons often transmit the virus before developing any signs of disease (Link). In contrast, most transmissions of SARS and MERS occurred in hospitals, so at a time, the infected individual was already seeking medical care due to symptoms (Link). Thus, it was easier to contain these viruses as compared with SARS-CoV-2. Over 8000 people fell sick with SARS, and 774 died. No more reported cases have occurred since 2004 (26 countries) (Link). For MERS, 2578 confirmed cases and 888 deaths were recorded by October 2021 (27 countries) (Link).
The situation is dramatically different for SARS-CoV-2. By January 27, 2022, 360.578.392 confirmed COVID-19 cases, and more than 5.6 million deaths had been reported globally (Link). And the number of cases is currently rocketing in many countries due to Omicron. The new and the 5th variant of concern (VOC) was first reported to the WHO on November 24, 2021, from South Africa (Link) and will soon be dominant globally.
After the successful efforts to rapidly develop multiple vaccines against SARS-CoV-2, the question of when and if this pandemic will ever end remains, especially in light of the new wave caused by Omicron. Indeed, there is reason to believe that we are transitioning into an endemic situation. There is growing evidence that Omicron has a milder course of the COVID-19 disease and lower mortality. The progressed vaccination campaign and natural immunity through infections support this situation.
On the way to becoming endemic, though, and afterward, we must constantly prove and rely on the protective measures. Above all, we need vaccination on a global scale.
Compared with previous variants, Omicron shows more mutations, especially in the spike protein’s receptor-binding domain (RBD) (Link). Therefore, the protective antibodies produced in the humoral arm of immunity, either via infection or vaccination, can no longer bind to these surface proteins of the virus – the key no longer fits into the lock. Respectively, the effectiveness of spike protein targeting vaccines drops significantly (Link). However, being twice vaccinated or even boostered with Biontech-Pfizer’s COVID-19 vaccine Corminaty® or Moderna’s Spikevax® still clearly reduces the risk of severe illness (Link). The reason for this mode of protection roots in another arm of the immunity: cellular immunity, led by T cells, that can still recognize and clear the virus (Link).
From left to right: Schematic presentation of the coronavirus, the spike protein on its surface, the receptor-binding domain (RBD) in the spike protein, and a fragment of the RBD.
Among other functions, T cells act as killer cells that identify, attack, and destroy infected cells, limiting the infection’s spread. So compared with antibodies, which prevent the virus from entering the cells, they have a different immunizing effect. While antibodies protect from infection, T cells are more critical in reducing the severity of the disease, which appears to be increasingly crucial for COVID-19. An advantage of T cells is that the induced cellular immunity is long-lasting.
Another fundamental difference between antibodies and T cells is the part of the virus they recognize, the antigen: Antibodies identify specific sites on the outer proteins (e.g., spike protein) of the virus based on structural information (key-lock-principle), whereas the T cell recognizes the chemical sequence of small protein fragments, so-called peptides. Because these peptides can originate from internal proteins of the virus, which are less prone to mutations, T cells can still respond to emerging variants like Omicron (Link).
Schematic presentation of antibody-mediated humoral immunity (left) vs. T cell-induced (right) cellular immunity.
For example, researchers identified hCoV-cross-reactive T cells in various studies (Link or Link). In other words, coronavirus-specific T cells developed upon infection with previous and harmless coronaviruses share peptides with SARS-CoV-2 and are therefore also reactive against the latter providing evidence of durable protective immunity. On top of that, recent studies provided evidence that these virus-specific T cells can even clear the infection before a measurable outbreak takes place (Link).
In sum, T cell-based vaccines may pave the way out of the ongoing and future corona pandemics because they can provide durable and mutation-resistant protection against multiple viral strains.
Indeed, companies develop several T cell vaccine candidates against SARS-CoV-2, which directly target cellular immunity. They consist of a set of peptides covering different parts of the virus. The peptides are typically mixed with an adjuvant, an immune-potentiating agent because the immune system wouldn’t recognize the peptide as foreign without it. The peptide, which is essentially a tiny protein, appears like food to the body — and the adjuvant acts like an alert system to engage the immune response against these viral peptides.
A Germany-originating T cell vaccine candidate against SARS-CoV-2 just passed a clinical phase I trial (Link). The so-called CoVac-1 consists of six peptides, representing fragments of five different SARS-CoV-2 sub-proteins. The peptides are mixed with another synthetic peptide (XS15) and Montanide (a mixture of mineral oil and surfactant), serving as adjuvants and stabilizing the compounds. The vaccine was well-tolerated and induced T cells that recognized all currently circulating SARS-CoV-2 variants, including Omicron. This outcome emphasizes the potential to address all current and upcoming variants with a T cell vaccine. CoVac-1 addresses immune-compromised persons who cannot produce sufficient antibodies with the presently given vaccines. However, such a vaccine is likely to become more relevant for the general population, as also expected by others (Link).
The ability to address both structural and non-structural SARS-CoV-2 proteins is highly promising in vaccine development, as it enables potency against current and upcoming variants. The company Emergex Vaccines, for example, develops a vaccine with durable protection against the entire lineage of SARS-like coronaviruses by combining peptides from the current virus with that of SARS-CoV-1 (Link).
Yet, developers must show the efficacy of these peptide vaccines in phase II and III clinical trials. One potential issue here is the potency of the adjuvant when solely mixed with the peptides. More robust responses are likely to occur when the adjuvant is chemically bound to the peptide.
At this point, Belyntic comes into play. We are also developing a peptide-based vaccine platform called ImmunoPEC (Link). In this approach, AI-predicted peptides that address T cell-mediated immune response to the particular pathogen are chemically attached to adjuvants to generate an effective and long-lasting immunity. Our proprietary Peptide Easy Clean (PEC) technology plays a vital role in efficiently manufacturing such complex peptides. Our envisioned vaccine cocktail consists of fully synthetic single molecules that are highly stable at ambient temperature, allowing for global supply. We apply the platform for developing a COVID-19 vaccine in collaboration with the University Hospital Bonn.
First of all, preparedness is fundamental to successfully fight any health threats in the future on a national or a global scale (Link). It should include robust surveillance systems for newly emerging viruses, risk assessment and analysis, and fast communication to allow proper and rapid action. Moreover, we need better communication between the scientific community and the public to eradicate/fight circulating misinformation.
Another lesson learned is that coalitions of companies, organizations, and politics are vital to act fast in the fight against a global threat (e.g., COVID-19 healthcare coalition (Link), COVID-19 global evaluation coalition (Link), COVID-19 clinical research coalition (Link)). Drug manufacturing robust to global supply shortages is essential to secure medicine supply.
The development, manufacturing, and distribution of RNA-based vaccines was a breakthrough. Yet, we need more effective vaccines and therapies. The establishment of new vaccine technologies like our ImmunoPEC platform might be the key to developing potent vaccines in the future with pan-corona and long-lasting protection without the need for seasonal boosters (Link).