key: cord-278260-3o91v72a authors: Halstead, Scott B; Katzelnick, Leah title: COVID 19 Vaccines: Should we fear ADE? date: 2020-08-12 journal: J Infect Dis DOI: 10.1093/infdis/jiaa518 sha: doc_id: 278260 cord_uid: 3o91v72a Might COVID 19 vaccines sensitize humans to antibody dependent enhanced (ADE) breakthrough infections? This outcome is unlikely because coronavirus diseases in humans lack the clinical, epidemiological, biological or pathological attributes of ADE disease exemplified by the dengue viruses (DENV). In contrast to DENV, SARS and MERS CoVs predominantly infect respiratory epithelium, not macrophages. Severe disease centers on older persons with pre-existing conditions and not young infants or individuals with previous coronavirus infections. Live virus challenge of animals given SARS or MERS vaccines has resulted in vaccine hypersensitivity reactions (VAH), similar to those in humans given inactivated measles or respiratory syncytial virus vaccines. Safe and effective COVID 19 vaccines must avoid VAH. A c c e p t e d M a n u s c r i p t 3 Introduction. Not since pandemic smallpox or the 1918 influenza have humans confronted a epidemic viral pathogen as successful as SARS CoV-2, a member of a family of viruses that cause serious diseases in many vertebrates. [1] It has proved difficult to achieve robust vaccine protection against avian, bovine, porcine, canine and feline coronaviruses, failures sometimes attributed to "antibody dependent enhancement (ADE)." [2] The possibility that a SARS CoV-2 vaccine may sensitize recipients to ADE has received considerable scrutiny. [3] On inspection, ADE is not one but two vaccine-related immunopathological phenomena: intrinsic ADE (iADE) and vaccine hypersensitivity (VAH). iADE describes interactions between IgG antibody and microbial pathogen immune complexes that attach to Fc receptors to initiate infection but also enhance replication of the microbe by suppressing innate cellular immune defenses. [4, 5] VAH was first described in humans in the early 1960s, after formalin-inactivated measles vaccines were introduced in the US and Europe. Within months large numbers of vaccinated children developed a severe breakthrough disease, called "atypical measles." [6] A similar outcome, "vaccine associated enhanced respiratory disease (VAERD)," was observed in infants, 4 -12 months of age, who were given formalininactivated respiratory syncytial virus (RSV) and a few months later infected by RSV. [7] The outcomes observed were attributed to delayed type hypersensitivity and/or an Arthus reaction. [8] Lung lesions revealed damage to parenchymal tissue, a pulmonary neutrophilia with abundant macrophages and lymphocytes and excess eosinophils. From studies in laboratory animals, it is thought that formalin de-conformed viral antigens raised nonprotective antibodies that led to a Th2 polarization of the immune response and a deficit of cytotoxic T cells. It was also the case that mice immunized with RSV inactivated with UV radiation, a purified fusion (F) protein, or a vaccinia-RSV replicative construct experienced similar pathology following challenge with wild-type virus. A similar pathological response has repeatedly accompanied live virus challenge in several species of laboratory animals A c c e p t e d M a n u s c r i p t 4 vaccinated with SARS and MERS CoV constructs, with and without adjuvants. [9, 10] VAH may best be defined as a Coombs type III antigen hypersensitivity. It should be emphasized there is no formal proof that VAERD is antibody mediated. The mechanism(s) of the postmeasles vaccine disease enhancement and its similarity to VAERD are not known. The biological behavior of some coronaviruses in non-human species together with evidence that human coronavirus antibodies enhanced infection of SARS or MERS CoVs in Fc receptor-bearing cells, in vitro, have led to speculations that ADE contributes to disease severity in humans. [11] It has been reported that high levels of SARS CoV-1 IgG antibodies circulated in severe SARS cases and that anti-S IgG neutralizing antibody (NAb) responses developed significantly faster after the onset of clinical symptoms in fatal compared with recovered cases leading some to attribute enhanced tissue damage to ADE. [12] Because sera from SARS or MERS vaccinated animals sera enhanced CoV infections, in vitro, it was assumed that post-vaccination pathologies, too, were ADE responses. [13] DENGUE ADE If SARS or MERS infection outcomes are affected by iADE they should have epidemiological and disease features in common with DENV. These are compared in Table 1 . In vivo, iADE requires an initial immunological event, termed "sensitization." In dengue, this occurs in three settings: 1) first infections, [14] 2) multitypic dengue antibodies passively transferred to infants (high antibody levels protect, low levels enhance), [15] and 3) vaccination resulting in incomplete protective immunity. [16, 17] Crucial to the occurrence of iADE is the circulation of four antigenically related DENVs. After a first infection, there is a 1 -2 year period of relative cross protection after which heterotypic DENV infection may cause severe disease. [18] Third or fourth sequential infections are not pathogenic. Pre-outbreak age-specific distributions of dengue antibodies control age-specific ADE disease attack rates. During heterotypic infections, viremias may be enhanced early but as illness progresses the titers and duration of viremias are shortened. [19] A c c e p t e d M a n u s c r i p t 5 Dengue disease is a serious and widespread global health problem. In many dengue endemic countries there is an estimated 2% lifetime risk of hospitalization for enhanced dengue disease. [20] Severe DENV iADE infections are short duration illnesses that elicit a stereotypical clinical course: an abrupt onset of fever and generalized symptoms followed around the time of defervescence by a rapid loss of fluid from the vascular compartment and, in turn, anoxia, shock and gastrointestinal hemorrhage. [21] The first suggestion of an immunopathology was finding that DENV infected peripheral blood leukocytes (PBL) from dengue-immune monkeys and humans but not PBLs from non-immune donors. [22] Severe DENV infections in infants implied that antibodies were etiological factors, a hypothesis confirmed when antibody mediated enhanced DENV infection was produced in monkeys. [23] Peak viremia titers observed early in illness are predictive of severe dengue in humans. [19] Careful pathologic studies identified splenic and lymph node monocytes, macrophages and dendritic cells as major targets of DENV infection. [24] Fluid loss from the vascular compartment is attributed to capillary damage caused by circulating toxic viral protein (nonstructural protein 1 -NS1). [25] In humans, disruption of endothelial glycocalyx components by NS1 correlates with plasma leakage during severe DENV infection. [26] DENV NS1-induced endothelial cell intrinsic pathway vascular leakage is related to loss of integrity of endothelial glycocalyx components both in vitro and in vivo and is independent of inflammatory cytokines. [27] Two corollary iADE phenomena have been described: 1) passively acquired dengue antibodies efficiently enhance infection/disease and 2) disease severity rates may increase rapidly during epidemics. Severe dengue accompanies first infections in infants circulating dengue antibodies acquired from multi-immune mothers. [28] During the course of secondary DENV 2 epidemics in Cuba in 1981 and 1997, disease severity increased month to month. It has been suggested that a single amino acid mutation in non-structural protein 1 (NS1) may observed as early as 4 days after onset of illness. It is thought that competent T cell immunity is essential for recovery. [34] While many clinical and pathological features are shared by SARS, MERS and COVID 19, lungs from patients with COVID-19 show distinctive severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with COVID-19 showed widespread thrombosis, microangiopathy and a reactive angiogenesis. [35] Indeed, there is growing evidence of thromboembolic phenomena in COVID 19. [36] In severe and fatal SARS and MERS the dominance of the inflammatory response gave rise to the concept that cellular damage was due to a "cytokine storm." [37] Because cytokines are stimulated by viral infection itself, it is difficult to distinguish between cytokines as cause or effect of infection. "Cytokine storm" has also been invoked as a pathogenic mechanism in dengue, instead, capillary damage results from a circulating viral toxin. [25] Concluding Remarks: With others, we conclude that the differences in clinical, epidemiological and pathological features of SARS and DENV diseases suggest that iADE does not contribute to the severity of natural human coronavirus infections. [39] A question asked frequently is whether SARS or MERS CoV infections convey solid protective immunity. Viral respiratory infections often fail to protect the respiratory tract from reinfection by the same organism. Among immune individuals, respiratory tract superinfections occur frequently, but, usually without systemic disease. [40] For example, natural and vaccine immunes were re-infected with measles or rubella viruses and these infections may contribute to the spread of virus. [41] VAH is a post-vaccination outcome that may be associated with non-protective antibodies. VAH is a complex and poorly defined immunopathology. Several different SARS and MERS vaccines have been shown to elicit a post-challenge VAH in laboratory animals. Ominously, when SARS-CoV-1-immune monkeys were challenged with homologous virus most animals had evidence of lung inflammation. [40] It is important to note that inactivated measles vaccine and Dengvaxia exhibited short-term protection. [6, 16] A central challenge to SARS CoV-2 vaccine development will be differentiating early from sustained protection and will be greatly aided by a SARS CoV-2 model of VAH in laboratory animal models. Recognition of vaccine constructs that achieve solid protection in humans might be Controlled by prevalence of 1 st DENV infection antibodies. [47] No antibody effect observed ADE with passive Antibody 5 -11 month-old infants born to DENVimmune mothers [47] Not observed Viral pathogenicity Increases month to month; single mutation controls [49] Not observed Vaccine ADE Dengvaxia raises non-protective (ADE) antibodies, sensitizing non-immunes [16, 17] Challenge virus produces VAH in vaccinated animals [9, 10, 50] Animal coronavirus vaccines: lessons for SARS An update on feline infectious peritonitis: virology and immunopathogenesis A perspective on potential antibody-dependent enhancement of SARS-CoV-2 Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes How Innate Immune Mechanisms Contribute to Antibody-Enhanced Viral Infections Altered reactivity to measles virus. 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