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Strategies to prevent SARS-CoV-2-Mediated Eosinophilic Disease in Association with COVID-19 Vaccination and Infection

Lab Rat Posters | RedbubbleA vaccine to protect against COVID-19 is urgently needed. Such a vaccine should efficiently induce high-affinity neutralizing antibodies which neutralize SARS-CoV-2, the cause of COVID-19. However, there is a concern regarding both vaccine-induced eosinophilic lung disease and eosinophil-associated Th2 immunopotentiation following infection after vaccination. Here, we review the anticipated characteristics of a COVID-19 vaccine to avoid vaccine-associated eosinophil immunopathology.

Keywords: COVID-19, Eosinophil, Immunity, Immunopathology, SARS-CoV-2, Vaccination

Introduction

COVID-19 is a new infectious disease caused by a coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. The virus exhibits high infectivity and can cause a broad spectrum of symptoms and severity [2]. To limit the damage of COVID-19, primary efforts focus on confinement, with physical distancing, wearing face masks, and hygiene measures [3]. However, although these measures help against viral spread, they cause limitations in our personal and professional lives. Moreover, there is a constant risk of viral outbreaks with severe consequences for health and economics. Therefore, rapid immunization of the world's population against SARS- CoV-2 is needed and vaccines are currently being developed world-wide [4]. There are several strategies to develop a vaccine such as live-attenuated or inactivated viruses, viral vector-containing nanoparticles or virus-like particles, subunit components, proteins/peptides, RNA, DNA, or even viable cells. These strategies are reviewed elsewhere [4]. In this article, we would like to point out the risk of eosinophil-associated immunopathology following infection after SARS-CoV-2 vaccination as well as strategies for its prevention.

COVID-19 and Eosinophils

Eosinophils represent a subpopulation of granulocytes which can mediate immunopathology in eosinophilic diseases such as bronchial asthma, eosinophilic esophagitis, and hypereosinophilic syndromes [5]. Eosinophils are believed to exhibit antibacterial and antiviral effector functions as well as protecting against parasites [67]. Although rhinovirus, respiratory syncytial virus (RSV), and influenza virus are common triggers of viral-induced asthma exacerbation, neither SARS-CoV-1 nor SARS-CoV-2 have been identified as risk factors for asthma exacerbations [89]. Interestingly, COVID-19 patients exhibited eosinopenia while eosinophil levels increased in association with improved clinical status [9]. Moreover, in a patient with COVID-19, a lymphocytic infiltration of the lungs was observed, whereas no eosinophil infiltration was detected [10]. Taken together, although the available data are very limited, eosinophils do not seem to play either a protective or pathogenic role in COVID-19 under normal circumstances.

But how about the role of eosinophils during coronavirus vaccination? SARS-CoV-1 vaccines have been shown to induce pulmonary eosinophilia in ferrets [11], monkeys [11], and mice [12] after viral challenge. Eosinophil-associated type 2 inflammation also occurred with SARS-CoV-1 reinfection in monkeys [13]. Eosinophil-associated pulmonary disease was also seen subsequent to infection after RSV vaccination [14]. Therefore, there is the possibility that SARS-CoV-2 vaccines might cause a similar vaccine-associated immunopathology.

Immune Responses in Association with Coronavirus Vaccination

The most promising strategy for reaching immunity against COVID-19 is to induce the production of virus-neutralizing antibodies (Fig. (Fig.1).1). Such antibodies usually block the interaction of the virus with its cellular receptor. The cellular receptor of SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2) [15]. Therefore, the primary immune mechanism for avoiding infection seems to be by blocking viral attachment to ACE2. Indeed, most COVID-19 vaccine candidates follow this strategy [16]. The obvious isotype to be induced is IgG, particularly the protective IgG1 and IgG3 subclasses. However, since the virus targets mucosal surfaces, IgA induction might also be beneficial. The formulation of the vaccine candidate with Toll-like receptor (TLR) 7/8 and TLR9 ligands to the vaccine might promote IgA production [1718] and, in addition, may favor type 1 immune responses (Fig. (Fig.1)1) [19].

 
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An illustrated presentation of the anticipated type 1 and type 2 immune responses by SARS-CoV-2, the spike (S) protein and its receptor binding domain (RBD). Based on information about SARS-CoV-1, the whole virus and the complete S protein induce type 2 immune responses. In contrast, RBD does not induce type 2 inflammation. It is suggested that a COVID-19 vaccine should contain the RBD and additional Th1-promoting molecules (dashed box). High-affinity SARS-CoV-2 neutralizing antibodies are the best protection against virus-induced type 2 eosinophilic inflammation upon re-challenge.

To obtain specific antibody production, B cells require “help” from CD4+ T cells. The induction of CD4+ T-helper cells is often not rate limiting in vaccination, most likely because low numbers of these cells are already sufficient for antibody production. Nevertheless, low responders to vaccination often fail to mount IgG responses due to insufficient CD4+ T-cell “help”. Since T-cell help can be provided by CD4+ T cells with other antigen specificities, vaccines can be supplemented with microbial proteins or peptides to which most humans are already immunized [20]. The immune response to these antigens will be strong because boosting of previously primed and established CD4+ T cells is more efficient than priming. Such microbial antigens may also skew the immune response towards T-helper type 1 polarization (Fig. (Fig.1)1) [19].

A type 1 immune response might also be attained by viral vectors or innate stimulators with type 1 polarization capabilities [212223]. For instance, nanoparticles and virus-like particles can be designed to contain molecules that stimulate innate immunity to enhance T-helper 1 and to block T-helper 2 polarization [24].

The type of T-helper immune response may also depend on the antigen. Immunization with inactivated SARS-CoV-1 causes eosinophilic infiltration following viral re-exposure in mice [25]. Immunization with the whole spike (S) protein, which is responsible for binding to ACE2, also triggered type 2 inflammation including eosinophilia after viral challenge in mice [11]. In contrast, at least in the case of SARS-CoV-1, immunization with the so-called receptor binding domain, which is a particular part within the S protein, induced neutralizing antibodies in the absence of a type 2 immune response (Fig. (Fig.1)1) [26].

Increased immune pathology may also occur via antibodies induced by the vaccine (Fig. (Fig.2).2). For example, an antibody enhancement of infection may occur when antibodies promote viral uptake via Fc receptors. However, there is no evidence that such a mechanism occurs with SARS-CoV-1 [27]. On the other hand, antibodies may also activate immunoreceptor tyrosine-based activation motifs within the cytoplasmic domain of Fc receptors, resulting in increased secretion of pro-inflammatory cytokines by macrophages and dendritic cells. Such a scenario, however, requires a high viral load which is unlikely to occur if vaccine-induced neutralizing antibodies are present. Therefore, antibody-dependent enhancement is not expected to cause problems for COVID-19, but eosinophil-mediated immunopathology following SARS-CoV-2 vaccination and infection may be at the heart of the problem (Fig. (Fig.22).

 
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Vaccination may enhance disease by induction of IgG antibodies (left) or Th2 cells (right). a IgG antibodies may enhance infection if the cellular target of infection expresses Fcγ receptors. b Alternatively, IgG antibodies may enhance antigen presentation by targeting viral particles to professional antigen-presenting cells, enhancing inflammation. c Th2 cells may recruit eosinophils to the lung, also causing enhanced infection. As SARS-CoV-2 does not infect Fcγ receptor-expressing cells and viral load is expected to be reduced in vaccinated individuals, IgG antibodies are not expected to cause enhanced disease, in particular not neutralizing antibodies. Th2 cell-induced eosinophilia, may, however, be a major concern, and therefore induction of Th2 cells by vaccination should be avoided.

Taken together, COVID-19 vaccines should induce high-affinity neutralizing antibodies. Moreover, they should polarize the T-cell response towards type 1 immunity and avoid the stimulation of cytokines which induce T-helper 2 immunity. To avoid type 2 inflammatory responses, careful selection of the vector and the antigen is required. The addition of TLR ligands and other molecules stimulating type 1 immunity might be helpful with respect to sufficient CD4+ T-cell help for antibody production as well as suppressing unwanted type 2 immunity-causing eosinophilia. It should be noted, however, that it is only partially possible to predict vaccine efficacy and safety [28]. Due to its urgency, COVID-19 vaccination should be given the highest priority.

Disclosure Statement

M.F.B. owns shares in Saiba GmbH which is involved in the development of a vaccine against COVID-19. H.-U.S. and A.V.K. declare no conflicts of interest.

Funding Sources

Research of H.-U.S. is supported by a grant from the Swiss National Science Foundation (grant No. 310030_184816). A.V.K. is supported by the Russian Excellence Project «5–100». Research of M.F.B. is supported by the Swiss National Science Foundation (grant No. 310030_179459).

References

1. Hoehl S, Rabenau H, Berger A, Kortenbusch M, Cinatl J, Bojkova D, et al. Evidence of SARS-CoV-2 infection in returning travelers from Wuhan, China. N Engl J Med. 2020 Mar;382((13)):1278–80. [PMC free article] [PubMed[Google Scholar]
2. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. China Medical Treatment Expert Group for Covid-19 Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020 Apr;382((18)):1708–20. [PMC free article] [PubMed[Google Scholar]
3. Cheng VC, Wong SC, Chen JH, Yip CC, Chuang VW, Tsang OT, et al. Escalating infection control response to the rapidly evolving epidemiology of the coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 in Hong Kong. Infect Control Hosp Epidemiol. 2020 May;41((5)):493–8. [PMC free article] [PubMed[Google Scholar]
4. Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 vaccines at pandemic speed. N Engl J Med. 2020 May;382((21)):1969–73. [PubMed[Google Scholar]
5. Simon HU, Yousefi S, Germic N, Arnold IC, Haczku A, Karaulov AV, et al. The cellular functions of eosinophils: Collegium Internationale Allergologicum (CIA) Update 2020. Int Arch Allergy Immunol. 2020;181((1)):11–23. [PMC free article] [PubMed[Google Scholar]
6. Yousefi S, Gold JA, Andina N, Lee JJ, Kelly AM, Kozlowski E, et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat Med. 2008 Sep;14((9)):949–53. [PubMed[Google Scholar]
7. Domachowske JB, Dyer KD, Bonville CA, Rosenberg HF. Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus. J Infect Dis. 1998 Jun;177((6)):1458–64. [PubMed[Google Scholar]
8. Yin Y, Wunderink RG. MERS, SARS and other coronaviruses as causes of pneumonia. Respirology. 2018 Feb;23((2)):130–7. [PMC free article] [PubMed[Google Scholar]
9. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020 Feb;:all.14238. [PubMed[Google Scholar]
10. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Apr;8((4)):420–2. [PMC free article] [PubMed[Google Scholar]
11. Tseng CT, Sbrana E, Iwata-Yoshikawa N, Newman PC, Garron T, Atmar RL, et al. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PLoS One. 2012;7((4)):e35421. [PMC free article] [PubMed[Google Scholar]
12. Deming D, Sheahan T, Heise M, Yount B, Davis N, Sims A, et al. Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants. PLoS Med. 2006 Dec;3((12)):e525. [PMC free article] [PubMed[Google Scholar]
13. Clay C, Donart N, Fomukong N, Knight JB, Lei W, Price L, et al. Primary severe acute respiratory syndrome coronavirus infection limits replication but not lung inflammation upon homologous rechallenge. J Virol. 2012 Apr;86((8)):4234–44. [PMC free article] [PubMed[Google Scholar]
14. Clark CM, Guerrero-Plata A. Respiratory syncytial virus vaccine approaches: a current overview. Curr Clin Microbiol Rep. 2017 Dec;4((4)):202–7. [PMC free article] [PubMed[Google Scholar]
15. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020 Apr;181((2)):271–280.e8. [PMC free article] [PubMed[Google Scholar]
16. Zhang J, Zeng H, Gu J, Li H, Zheng L, Zou Q. Progress and Prospects on Vaccine Development against SARS-CoV-2. Vaccines (Basel) 2020 Mar;8((2)):E153. [PMC free article] [PubMed[Google Scholar]
17. Meiler F, Klunker S, Zimmermann M, Akdis CA, Akdis M. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy. 2008 Nov;63((11)):1455–63. [PubMed[Google Scholar]
18. Bessa J, Bachmann MF. T cell-dependent and -independent IgA responses: role of TLR signalling. Immunol Invest. 2010;39((4-5)):407–28. [PubMed[Google Scholar]
19. Johnson TR, Rao S, Seder RA, Chen M, Graham BS. TLR9 agonist, but not TLR7/8, functions as an adjuvant to diminish FI-RSV vaccine-enhanced disease, while either agonist used as therapy during primary RSV infection increases disease severity. Vaccine. 2009 May;27((23)):3045–52. [PMC free article] [PubMed[Google Scholar]
20. Zeltins A, West J, Zabel F, El Turabi A, Balke I, Haas S, et al. Incorporation of tetanus-epitope into virus-like particles achieves vaccine responses even in older recipients in models of psoriasis, Alzheimer's and cat allergy. NPJ Vaccines. 2017 Oct;2((1)):30. [PMC free article] [PubMed[Google Scholar]
21. Bode C, Zhao G, Steinhagen F, Kinjo T, Klinman DM. CpG DNA as a vaccine adjuvant. Expert Rev Vaccines. 2011 Apr;10((4)):499–511. [PMC free article] [PubMed[Google Scholar]
22. Vasilakos JP, Tomai MA. The use of Toll-like receptor 7/8 agonists as vaccine adjuvants. Expert Rev Vaccines. 2013 Jul;12((7)):809–19. [PubMed[Google Scholar]
23. Martins KA, Bavari S, Salazar AM. Vaccine adjuvant uses of poly-IC and derivatives. Expert Rev Vaccines. 2015 Mar;14((3)):447–59. [PubMed[Google Scholar]
24. Jegerlehner A, Maurer P, Bessa J, Hinton HJ, Kopf M, Bachmann MF. TLR9 signaling in B cells determines class switch recombination to IgG2a. J Immunol. 2007 Feb;178((4)):2415–20. [PubMed[Google Scholar]
25. Bolles M, Deming D, Long K, Agnihothram S, Whitmore A, Ferris M, et al. A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. J Virol. 2011 Dec;85((23)):12201–15. [PMC free article] [PubMed[Google Scholar]
26. Jiang S, Bottazzi ME, Du L, Lustigman S, Tseng CT, Curti E, et al. Roadmap to developing a recombinant coronavirus S protein receptor-binding domain vaccine for severe acute respiratory syndrome. Expert Rev Vaccines. 2012 Dec;11((12)):1405–13. [PMC free article] [PubMed[Google Scholar]
27. Yang ZY, Werner HC, Kong WP, Leung K, Traggiai E, Lanzavecchia A, et al. Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses. Proc Natl Acad Sci USA. 2005 Jan;102((3)):797–801. [PMC free article] [PubMed[Google Scholar]
28. Plotkin SA. Updates on immunologic correlates of vaccine-induced protection. Vaccine. 2020 Feb;38((9)):2250–7. [PubMed[Google Scholar]
 
 

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