30th September 2020

By Eszter Nagy, MD PhD, CEO of CEBINA

What is currently known about the adaptive immune response to SARS-CoV-2, and how can this increasing knowledge help in designing a safe and effective coronavirus vaccine? An overview of the most recent findings in the unprecedented race for fighting COVID-19.

The ultimate solution to the COVID-19 pandemic is expected to be a safe and effective vaccine that protects against the severe form of the disease and ultimately gives rise to herd immunity.

The general public is eagerly waiting for a definite answer when such vaccines become available. Although even the timeframe required for mass production of a COVID-19 vaccine is debated, less attention is focused on the question whether the most advanced vaccines currently tested in large-scale Phase 3 efficacy and safety trials scan fulfill the above requirements. The speed and magnitude of COVID vaccine development we are experiencing is unprecedented in human history. The most advanced vaccines have been initiated early this year and are already in Phase 3 testing. This is a remarkable achievement. On the other hand, the expedited vaccine development has not allowed enough time to gather sufficient research data to really understand what is required for protective immunity against the SARS-CoV-2 virus infection. The advanced vaccines are based solely on the Spike protein (S-protein) as vaccine antigen and assume that neutralizing antibodies are the main effectors of protection. The way of delivering this antigen and presenting it to the immune system is different among these vaccines. The S-protein is the most variable antigen among coronaviruses, and most likely induces species/strain specific responses. Even more concerning is the observation in animal models and in certain human cases, the presence of disease-enhancing antibodies connected to the S1 (N-terminal part) of the S-protein, which has to be carefully looked at for vaccine safety.

While in vitro assays and animal models are indicative for effectiveness, translational research looking at the human immune response to natural coronavirus infections is very important to understand what immune response the vaccines should induce in humans. Understanding the elements of natural protection, a pre-existing immunity some individuals have, is particularly informative. It is known that not everybody contracts SARS-CoV-2 infection upon being exposed to an infected person (remains COVID negative in nasal and throat swabs). It is also strongly established that a significant portion of the population who become infected (approximately 20%), colonized in the nose, the primary site of SARS-CoV-2 infection, do not even develop symptoms. Another significant portion develops mild or moderate symptoms but does not progress to disease, especially pneumonia.

The antibody response to SARS-CoV-2 in infected individuals is very variable and short-lived. It is believed to be true for coronaviruses in general; an increase in specific antibodies is waning quite quickly, explaining the high reinfection rate by seasonal common cold coronaviruses. Very low levels of SARS-CoV-2 cross-reactive antibodies are detected in the general population. Therefore, the early conclusion has been that pre-existing immunity to common cold coronaviruses is unlikely to provide protection from SARS-CoV-2 infection and COVID-19.

What about the other arm of the immune response: T cells? Recently published data suggest that the cellular arm of the immune system stores the memory of coronavirus encounter much longer than the humoral side (antibodies). T helper cells are very important for a robust (magnitude), effective (high affinity) and fast antibody response, especially evoking an immune memory response. A recently published research from the Max Planck Institute by Braun et al (doi: 10.1038/s41586-020-2598-9) could differentiate between the T helper (CD4+) responses induced by SARS-CoV-2 and seasonal common cold coronaviruses. The most significant finding of the study is that approximately 1/3 of the healthy test group, unexposed to SARS-CoV-2, has circulating T helper (CD4+) cells that recognize epitopes in the S-proteins of SARS-CoV-2. Moreover, the pattern of epitope recognition is different from that found in COVID patients and characterized by epitope sequences representing conserved coronavirus sequences mainly located in the S2 (C-terminal part) of the S-protein, while COVID patients mainly mount T cell response against epitopes in the S1 part, which is less conserved. The presence of cross-reactive T helper cell response recognizing SARS-CoV-2 in significant portion (40 to 60%) of individuals not exposed to SARS-CoV-2 is also reported by Grifoni et al (doi: 10.1016/j.cell.2020.05.015). Importantly, the T cell response is not only targeted against the S-protein, but also other major viral proteins, such as the M protein. These observations offer the possibility that pre-existing coronavirus cross-reactive T cells might translate to protection from SARS-CoV-2 infection upon exposure to the virus by evoking a rapid antibody response. This needs to be confirmed in larger cohorts and to correlate the presence of these T cells with clinical outcome, especially determining whether it can be the basis of resistance to infection (preventing colonization) and/or to the development of symptoms.

This finding is not totally unexpected based on experiences in the viral immunology field. For example, it is known that repeated exposure to the influenza virus can evoke cross-reactive T cell responses that provide protection/better disease outcome across different flu viruses emerging seasonally. This type of immune response is not generated by most influenza vaccines that induce only/mainly antibody response that is specific for the influenza virus covered by the actual seasonal flu vaccine.

Taken all these together, viral protein sequences representing and/or conserved across different coronaviruses (including both the common cold and pandemic strains) to be included in the vaccine antigen against COVID-19 is highly warranted.

CEBINA is working on such a vaccine by including different viral proteins beyond the S1-protein with the potential to induce cross-reactive T cell responses and by combining antigens from different coronaviruses. This vaccine approach offers the possibility of a broad-spectrum, pan-coronavirus vaccine against potential future pandemic and seasonal common cold coronaviruses.