Scientific evidence showing (partially or full) pre-existing immunity from previous corona virus infections (CCC) to new coronaviruses
- Common Cold Corona (CCC) virus infections through life, offers pre-immunity to new corona-viruses

By Michael Schultz, physiotherapist (PT), certified Stecco Fascial Manipulation Therapist Level III, Economist Bsc., Corporate Law Bsc.

1: December 2009
Greenbaum et al: Pre-existing immunity against swine-origin H1N1 influenza viruses in the general human population.

T cells are known to blunt disease severity. Therefore, the conservation of a large fraction of T-cell epitopes suggests that the severity of an S-OIV infection, as far as it is determined by susceptibility of the virus to immune attack, would not differ much from that of seasonal flu. These results are consistent with reports about disease incidence, severity, and mortality rates associated with human S-OIV

2:March 2019
Devarajan et al: Original Antigenic Sin: Friend or Foe in Developing a Broadly Cross-Reactive Vaccine to Influenza? Cell Host Microbe. 2019 Mar 13; 25(3): 354–355.

Published studies in both mice and man of naive B and CD4 T cells indicate that the aged make reduced responses (Goronzy and Weyand, 2013Haynes and Swain, 2012), but that memory cells generated in youth remain functional into old age. The reduced responses of naive cells and selection by encounters with multiple viral strains may together explain the greater emergence of dominant cross-reactive Abs later in life…

These studies reiterate the complex role of pre-existing Abs in shaping consequent immunity to vaccine and highlight the fact that experiments in animal models need to use mice with pre-existing influenza immunity if they are to reflect the human situation. Indeed, sequentially infected mice or pet store/feral mice (Huggins et al., 2019) have T and B profiles more like those in man….

original antigenic sin to broadly shared epitopes may prove to be an important asset in the aged, given their impaired immune response to new antigens. The presence of clonotypes that continue to persist even through exposures to drifted strains over the years lends hope that a universal influenza vaccine can be developed that could free individuals from the need to be immunized yearly.

The striking reduction with age in the generation of de novo Abs to vaccination suggests distinct strategies may be needed to vaccinate the young versus the middle-aged or elderly. Here the presence of memory to shared influenza determinants in older individuals could be an asset, providing some protection without new responses.

…This indicates "serological imprinting,” a.k.a. "original antigenic sin,” in which the Ab produced during an exposure to an infection or immunization dominates the repertoire through subsequent exposures. This phenomenon, recognized since 1960, has also been seen repeatedly in responses to influenza(Zhang et al., 2019). The study indicates both that broadly reactive anti-stalk Abs can develop in humans and that when they do, they can persist for several years. The dominant clonotypes represented over 70% of the anti-CA repertoire, suggesting that most of the response to yearly vaccination is composed of Abs from long-lived plasma cells or memory B cells generated previously.

Two key unanswered questions are how early in life the persistant repertoire is established and what is required to induce it. It is well known that live infection is much more effective at inducing neutralizing Ab responses in unimmunized individuals and that protection then lasts for years. In contrast, inactivated split vaccine induced weaker responses and more short-lived protection (He et al., 2015). This suggests that the vaccines do not effectively induce the pathways that generate long-lived plasma cells(LLPCs) and memory B cells. Lee et al. show that persistent Abs undergo increased SHM. SHM occurs in germinal centers and requires follicular helper T cells (TFH), both of which are highly augmented by highly activated antigen presenting cells (APCs) that secrete IL-6 (Brahmakshatriya et al., 2017). These APCs are most effectively induced by pathogen recognition during live infection. Thus, live infection is likely a key factor for establishing the persistent Ab repertoire.

3:June 2019
F. Krammer: The human antibody response to influenza A virus infection and vaccination. Nature reviewa immunology, 2019 Jun;19(6):383-397 
"The adaptive immune response to influenza virus infection is multifaceted and complex, involving antibody and cellular responses at both systemic and mucosal levels. Immune responses to natural infection with influenza virus in humans are relatively broad and long-lived, but influenza viruses can escape from these responses over time owing to their high mutation rates and antigenic flexibility. Vaccines are the best available countermeasure against infection, but vaccine effectiveness is low compared with other viral vaccines, and the induced immune response is narrow and short-lived. Furthermore, inactivated influenza virus vaccines focus on the induction of systemic IgG responses but do not effectively induce mucosal IgA responses. Here, I review the differences between natural infection and vaccination in terms of the antibody responses they induce and how these responses protect against future infection. A better understanding of how natural infection induces broad and long-lived immune responses will be key to developing next-generation influenza virus vaccines.

In conclusion, the antibody response to natural influenza virus infection seems to be broader and longer-lived than the antibody response induced by influenza virus vaccines.

June 2019
Vabret et al: Immunology of COVID-19: Current State of the Science. Immunity, 2020 Jun 16; 52(6): 910–941.
"However, these CD4 T cells lacked phenotypic markers of activation and were specific for C-terminal S protein epitopes that are highly similar to endemic human CoVs, suggesting that crossreactive CD4 memory T cells in some populations (e.g., children and younger patients that experience a higher incidence of hCoV infections) may be recruited into an amplified primary SARS-CoV-2-specific response (Braun et al., 2020). Similarly, endemic CoV-specific CD4 T cells were previously shown to recognize SARS-CoV1 determinants (Gioia et al., 2005). How previous infections with endemic CoV may affect immune responses to SARS-CoV-2 will need to be further investigated.

Studies of past coronavirus outbreaks involving SARS-CoV-1 and MERS-CoV have provided a foundation for our understanding. The pathology of severe cases of COVID-19 does indeed resemble certain immunopathologies seen in SARS-CoV-1 and MERS-CoV infections, like CRS.

The emerging epidemiological observation that significant proportions of individuals are asymptomatic despite infection not only reflects our current understanding that SARS-CoV-2 has a longer incubation period and higher rate of transmission than other coronaviruses, but also speaks to significant differences in the host immune response. 

… additional studies are needed to address how these immune differences across patients or between different types of coronavirus infections dictate who succumbs to disease and who remains asymptomatic.

5:November 2019
B. Agrawal: Heterologous Immunity: Role in Natural and Vaccine-Induced Resistance to Infections. Frontiers in Immunology, 2019; 10: 2631.
”Experimental and clinical evidence as well as theoretical constructs have clearly demonstrated that heterologous immunity or cross-reactivity of adaptive immune cells is not an isolated or accidental phenomenon, but rather a fundamental attribute of adaptive immunity, forming an integral part of the host defense system against pathogens under natural conditions….

In an individual, T and B cell repertoires originate by random VDJ gene rearrangement, however, their cross-reactivity and ability to respond to various antigens in a host is shaped to a large extent by exposure history and microbiota, and therefore, cross-reactivity remains largely unpredictable at the individual level. 

As stated earlier, cross-reactivity may vary among individuals and different sexes, and may largely remain unpredictable making application to vaccines which are usually population-based, not an easy task….

10. March 2020
World Health Organisation: Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected Interim guidance 13 March 2020.
"Although the majority of people with COVID-19 have uncomplicated or mild illness (81%),some will develop severe illness requiring oxygen therapy (14%) and approximately 5% will require intensive care unit treatment. Of those critically ill, most will require mechanical ventilation (2, 10). The most common diagnosis in severe COVID-19 patients is severe pneumonia”.

7:May 2020
Hussein et al: Novel COVID-19: A Comprehensive Review of Transmission, Manifestation, and Pathogenesis. Cureus,  2020 May; 12(5): e8184.
"Initial stages of COVID-19 present with symptoms that mimic the common cold and individuals may be asymptomatic carriers and thus, transmitting the virus to others. COVID-19, like other coronaviruses, presents with S glycoproteins on the membrane that plays an integral role in the virus binding with the angiotensin-converting enzyme 2 (ACE2) receptor. The ACE2 receptor is an intramembrane receptor on the type II pneumocytes, where the virus is able to replicate after getting endocytosed within the cytoplasm. As the viral load increases within the alveolar cell, the alveolar epithelial cell will burst, releasing the newly replicated viral RNA. Elderly individuals are at a greater risk of infection due to weakened immune systems and pre-existing medical conditions resulting in a compromised immune response, also increasing the susceptibility of infection. Infected individuals presenting with mild to moderate symptoms are recommended to self-isolate as the majority will recover without any intervention

8: June 2020
Karl Friston: Up to 80% not even susceptible to Covid-19. Unherd, F. Sayers, June 4, 2020
"Results have just been published of a study suggesting that 40%-60% of people who have not been exposed to coronavirus have resistance at the T-cell level from other similar coronaviruses like the common cold…the true portion of people who are not even susceptible to Covid-19 may be as high as 80%."

9:June 2020
A. Grifoni et al.: Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals.Cell, 2020 Jun 25; 181(7): 1489–1501.e15.

”Using HLA class I and II predicted peptide "megapools,” circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in 70% and 100% of COVID-19 convalescent patients.Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in 40%–60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating "common cold” coronaviruses and SARS-CoV-2”.


10:Jun 2020
Weiskopf et al.:  Phenotype of SARS-CoV-2-specific T-cells in COVID-19 patients with acute respiratory distress syndrome. SCIENCE IMMUNOLOGY, 26 Jun 2020 Vol 5, Issue 48
"We detected SARS-CoV-2-specific CD4+ and CD8+ T cells in 100% and 80% of COVID-19 patients, respectively. We also detected low levels of SARS-CoV-2-reactive T-cells in 20% of the healthy controls, not previously exposed to SARS-CoV-2 and indicative of cross-reactivity due to infection with ‘common cold’ coronaviruses”.

11:Juli 2020
Bert et al: SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature, 15 July 2020, pages457–462 (2020)
"We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37)… Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein. Understanding how pre-existing N- and ORF1-specific T cells that are present in the general population affect the susceptibility to and pathogenesis of SARS-CoV-2 infection is important for the management of the current COVID-19 pandemic”.

12:Juli 2020
F. Collins: Immune T Cells May Offer Lasting Protection Against COVID-19. National institute of Health, Blog, July 28th, 2020
"Much of the study on the immune response to SARS-CoV-2, the novel coronavirus that causes COVID-19, has focused on the production of antibodies. But, in fact, immune cells known as memory T cells also play an important role in the ability of our immune systems to protect us against many viral infections, including—it now appears—COVID-19. An intriguing new study of these memory T cells suggests they might protect some people newly infected with SARS-CoV-2 by remembering past encounters with other human coronaviruses. This might potentially explain why some people seem to fend off the virus and may be less susceptible to becoming severely ill with COVID-19.”

13:August 2020
Sette et al.: Pre-existing immunity to SARS-CoV-2: the knowns and unknowns. Nature Rewies Immunology, 2020 Aug;20(8):457-458 (Published online 2020 Jul 7)
"T cell reactivity against SARS-CoV-2 was observed in unexposed people… it is speculated that this reflects T cell memory to circulating ‘common cold’ coronaviruses”.

"In conclusion, it is now established that SARS-CoV-2 pre-existing immune reactivity exists to some degree in the general population. It is hypothesized, but not yet proven, that this might be due to immunity to CCCs*. This might have implications for COVID-19 disease severity, herd immunity”.

14:August 2020
T. Hicklin, Immune cells for common cold may recognize SARS-CoV-2. National Institute of Health NIH, August 18, 2020 (scientific article)

"Now a new study led by scientists at La Jolla Institute for Immunology (LJI)shows that memory helper T cells that recognize common cold coronaviruses also recognize matching sites on SARS-CoV-2, the virus that causes COVID-19. The research, published Aug. 4, 2020 in Science, may explain why some people have milder COVID-19 cases than others—though the researchers emphasize that this is speculation and much more data is needed."We have now proven that, in some people, pre-existing T cell memory against common cold coronaviruses can cross-recognize SARS-CoV-2, down to exact molecular structures,” says LJI Research Assistant Professor Daniela Weiskopf, Ph.D., who co-led the new study with LJI Professor Alessandro Sette, Dr. Biol. Sci. "This could help explain why some people show milder symptoms of disease while others get severely sick.”

15: August 2020
Bert et al.: SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature, 2020 Aug;584(7821):457-462
"In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein. Next, we showed that patients (n = 23) who recovered from SARS (the disease associated with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2.We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37).Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein”.

16: September 2020
Nelde et al.: SARS-CoV-2 T-cell epitopes define heterologous and COVID-19-induced T-cell recognition. Nature Immunology, 2020 Sept., 22, pages74–85 (2021)
"The first work identifying and characterizing SARS-CoV-2-specific and cross-reactive HLA class I and HLA-DR T-cell epitopes in SARS-CoV-2 convalescents (n = 180) as well as unexposed individuals (n = 185) and confirming their relevance for immunity and COVID-19 disease course…cross-reactive SARS-CoV-2 T-cell epitopes revealed pre-existing T-cell responses in 81% of unexposed individuals, and validation of similarity to common cold human coronaviruses provided a functional basis for postulated heterologous immunity in SARS-CoV-2 infection… intensity of T-cell responses and recognition rate of T-cell epitopes was significantly higher in the convalescent donors compared to unexposed individuals, suggesting that not only expansion, but also diversity spread of SARS-CoV-2 T-cell responses occur upon active infection.”

17: September 2020
P. Doshi.: Covid-19: Do many people have pre-existing immunity? British Medical Journal, 17;370:m3563
"Six studies have reported T cell reactivity against SARS-CoV-2 in 20% to 50% of people with no known exposure to the virus… in a study of donor blood specimens obtained in the US between 2015 and 2018, 50% displayed various forms of T cell reactivity to SARS-CoV-2… Researchers are also confident that they have made solid inroads into ascertaining the origins of the immune responses. "Our hypothesis, of course, was that it’s so called ‘common cold’ coronaviruses, because they’re closely related…we have really shown that this is a true immune memory and it is derived in part from common cold viruses.”

18:September 2020
Covid-19: Do many people have pre-existing immunity? British Medical Journal, 2020 Sep 17;370:m3563
"In late 2009, months after the World Health Organization declared the H1N1 "swine flu” virus to be a global pandemic, Alessandro Sette was part of a team working to explain why the so called "novel” virus did not seem to be causing more severe infections than seasonal flu.12

Their answer was pre-existing immunological responses in the adult population: B cells and, in particular, T cells, which "are known to blunt disease severity.”12 Other studies came to the same conclusion: people with pre-existing reactive T cells had less severe H1N1 disease.1314 In addition, a study carried out during the 2009 outbreak by the US Centers for Disease Control and Prevention reported that 33% of people over 60 years old had cross reactive antibodies to the 2009 H1N1 virus, leading the CDC to conclude that "some degree of pre-existing immunity” to the new H1N1 strains existed, especially among adults over age 60.15

The data forced a change in views at WHO and CDC, from an assumption before 2009 that most people "will have no immunity to the pandemic virus16 to one that acknowledged that "the vulnerability of a population to a pandemic virus is related in part to the level of pre-existing immunity to the virus.”17 But by 2020 it seems that lesson had been forgotten”.

19:October 2020
Beretta et al.: Is Cross-Reactive Immunity Triggering COVID-19 Immunopathogenesis? Frontiers in Immunology, 15 Oct. 2020; 11: 567710.
"There is also evidence that pre-existing T cell immunity to common cold coronaviruses can prime the response to SARS-CoV-2".

20: October 2020
Lipsitch et al: Cross-reactive memory T cells and herd immunity to SARS-CoV-2. Nature Reviews immunology, 2020 Oct.; 20(11): 709–713.
"If, indeed, cross-reactive T cells do reduce COVID-19 disease severity and/or SARS-CoV-2 shedding, it is possible that different populations (geographical or demographic) may differ with regard to disease severity or contagiousness because they have different degrees of prior exposure to coronaviruses6 and thus different degrees of T cell-mediated cross-reactive immunity”.

21: October 2020
Mateus et al.: Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science, 2020 Oct 2; 370(6512): 89–94.
”Mateus et al. found that the preexisting reactivity against SARS-CoV-2 comes from memory T cells and that cross-reactive T cells can specifically recognize a SARS-CoV-2 epitope as well as the homologous epitope from a common cold coronavirus. These findings underline the importance of determining the impacts of preexisting immune memory in COVID-19 disease severity”.

22:November 2020
Braun et al.: SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature, 2020 Nov; 587(7833):270-274
"Spike-protein-reactive T cell lines generated from SARS-CoV-2-naive healthy donors responded similarly to the C-terminal region of the spike proteins of the human endemic coronaviruses 229E and OC43, as well as that of SARS-CoV-2. This results indicate that spike-protein cross-reactive T cells are present, which were probably generated during previous encounters with endemic coronaviruses… the presence of spike-protein cross-reactive T cells in a considerable fraction of the general population may affect the dynamics of the current pandemic”.

23:December 2020
Faulkner et al.: Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science, 2020 Dec 11; 370(6522): 1339–1343.
"Our results from multiple independent assays demonstrate the presence of preexisting antibodies recognizing SARS-CoV-2 in uninfected individuals… SARS-CoV-2 spike glycoprotein (S)–reactive antibodies were detectable using a flow cytometry–based method in SARS-CoV-2–uninfected individuals and were particularly prevalent in children and adolescents”.

24:November 2021
Borrega et al: Cross-Reactive Antibodies to SARS-CoV-2 and MERS-CoV in Pre-COVID-19 Blood Samples from Sierra Leoneans. Viruses, 2021 Nov; 13(11): 2325.
"To characterize serological responses to coronaviruses in Sierra Leoneans, we tested blood samples collected BEFORE the reports in late 2019 of the first COVID-19 cases in Wuhan, China.

Blood samples from Sierra Leonean Lassa fever and Ebola survivors and their contacts collected before the first reported COVID-19 cases were assessed using enzyme-linked immunosorbent assays for the presence of antibodies binding to proteins of coronaviruses that infect humans. Results were compared to COVID-19 subjects and healthy blood donors from the United States. Prior to the pandemic, Sierra Leoneans had more frequent exposures than Americans to coronaviruses with epitopes that cross-react with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)

Prior exposures to coronaviruses that induce cross-protective immunity may contribute to reduced COVID-19 cases and deaths in Sierra Leone".

25:March 2022
Yu et al: Immunological memory to Common Cold Coronaviruses assessed longitudinally over a three-year period. BioRxiv, Preprint. 2022 Mar 2.
"The data presented herein are also relevant in the context of CCC*cross-reactivity with SARS-CoV-2. It has been shown that pre-existing T cell immunity elicited by past CCC exposures can influence COVID-19 responsiveness to vaccination and disease outcome3033,35. We found that while everybody had detectable antibody titers to CCC individuals varied in the level of T cell reactivity (possibly as a function of recent exposure, HLA type or other individual and environmental factors), and that the subjects with high CCC T cell reactivity, but not antibody titers, are those most likely to be associated with pre-existing SARS-CoV-2 immune reactivity. This is consistent with findings that CCC antibodies might not protect against SARS-CoV-2 infection or disease severity24,50 but T cells do30,51 (pre-print, not yet peer-reviewed)





*mCCC = Common Cold Coronavirus