Immune Responses against SARS-CoV-2—Questions and Experiences

Abstract

Understanding immune reactivity against SARS-CoV-2 is essential for coping with the COVID-19 pandemic. Herein, we discuss experiences and open questions about the complex immune responses to SARS-CoV-2. Some people react excellently without experiencing any clinical symptoms, they do not get sick, and they do not pass the virus on to anyone else (“sterilizing” immunity). Others produce antibodies and do not get COVID-19 but transmit the virus to others (“protective” immunity). Some people get sick but recover. A varying percentage develops respiratory failure, systemic symptoms, clotting disorders, cytokine storms, or multi-organ failure; they subsequently decease. Some develop long COVID, a new pathologic entity similar to fatigue syndrome or autoimmunity. In reality, COVID-19 is considered more of a systemic immune–vascular disease than a pulmonic disease, involving many tissues and the central nervous system. To fully comprehend the complex clinical manifestations, a profound understanding of the immune responses to SARS-CoV-2 is a good way to improve clinical management of COVID-19. Although neutralizing antibodies are an established approach to recognize an immune status, cellular immunity plays at least an equivalent or an even more important role. However, reliable methods to estimate the SARS-CoV-2-specific T cell capacity are not available for clinical routines. This deficit is important because an unknown percentage of people may exist with good memory T cell responsibility but a low number of or completely lacking peripheral antibodies against SARS-CoV-2. Apart from natural immune responses, vaccination against SARS-CoV-2 turned out to be very effective and much safer than naturally acquired immunity. Nevertheless, besides unwanted side effects of the currently available vector and mRNA preparations, concerns remain whether these vaccines will be strong enough to defeat the pandemic. Altogether, herein we discuss important questions, and try to give answers based on the current knowledge and preliminary data from our laboratories.

Post–COVID-19 syndrome and humoral response association after 1 year in vaccinated and unvaccinated patients

“…Vaccination against SARS-CoV-2 is a leading strategy to change the course of the COVID-19 pandemic worldwide, reducing the risk of infection, that of severe complications and the long-term effects in the case of a breakthrough infection ( 8 , 9 , 21 ). Moreover, vaccines have shown to increase immunogenicity, antibody titres, and reactogenicity in individuals with past infection compared with naive patients ( 22 ). Vaccine hesitancy of previously infected patients and long-haulers might be due to the belief that, having developed a dysregulated response to natural infection, that may be exacerbated by vaccination, and also to the perception that protection is acquired with previous infection, as observed in our cohort ( 11 , 23 ).…”

“…In contrast, the presence and persistence of RBD IgG stimulated by the vaccine in patients with hybrid immunity were not associated with post-COVID-19 compared with patients with natural infection. The immune response induced by vaccines is a highly targeted response to the Spike protein of the SARS-CoV-2 virus and may help the immune system to tackle the possible viral reservoir, reducing the chance of non-specific immune reactions and resetting the immune response ( 22 , 26 , 28 , 29 ). In contrast, the response triggered by natural infection is broader and may stimulate an excessive or dysregulated allo- and autoimmune response and uncontrolled inflammatory activity ( 22 , 30 ).…”

“…The immune response induced by vaccines is a highly targeted response to the Spike protein of the SARS-CoV-2 virus and may help the immune system to tackle the possible viral reservoir, reducing the chance of non-specific immune reactions and resetting the immune response ( 22 , 26 , 28 , 29 ). In contrast, the response triggered by natural infection is broader and may stimulate an excessive or dysregulated allo- and autoimmune response and uncontrolled inflammatory activity ( 22 , 30 ). Based on our data on vaccination and humoral response, the SARS-CoV-2 vaccination should be recommended in patients with a history of previous COVID-19 because further vaccine immune stimulation may not exacerbate sequalae nor produce an altered humoral response.…”

Anti-SARS-CoV-2 IgG against the S Protein: A Comparison of BNT162b2, mRNA-1273, ChAdOx1 nCoV-2019 and Ad26.COV2.S Vaccines

“…Studies have shown that a longer interval between two doses of a vaccine promotes a better immune response, as shown with the Pfizer/BioNTech vaccine. Data suggest that twodose vaccination may induce a better immune response to SARS-CoV-2 than homologous single-dose vaccination [40].…”

The Influence of Sex, Gender, and Age on COVID-19 Data in the Piedmont Region (Northwest Italy): The Virus Prefers Men

“…In the end, Transmembrane protease serine 2 (TMPRSS2) leads to continuous virus entry into cells, but its expression is upregulated by androgens [ 26 , 27 ]. Different immune responses, the RAAS system, ACE2, and TMPRSS2 role, and hormonal status are biological sex-related differences that count markedly towards the different COVID-19 progression among the sexes [ 28 , 29 , 30 , 31 , 32 ]. Gender, profoundly understudied, counts significantly in this context [ 33 ].…”