Ebola virus antibody decay–stimulation in a high proportion of survivors

Abstract

Neutralizing antibody function provides a foundation for the efficacy of vaccines and therapies [1][2][3] . Here, using a robust in vitro Ebola virus (EBOV) pseudo-particle infection assay and a well-defined set of solid-phase assays, we describe a wide spectrum of antibody responses in a cohort of healthy survivors of the Sierra Leone EBOV outbreak of 2013-2016. Pseudo-particle virus-neutralizing antibodies correlated with total anti-EBOV reactivity and neutralizing antibodies against live EBOV. Variant EBOV glycoproteins (1995 and 2014 strains) were similarly neutralized. During longitudinal follow-up, antibody responses fluctuated in a 'decay-stimulation-decay' pattern that suggests de novo restimulation by EBOV antigens after recovery. A pharmacodynamic model of antibody reactivity identified a decay half-life of 77-100 days and a doubling time of 46-86 days in a high proportion of survivors. The highest antibody reactivity was observed around 200 days after an individual had recovered. The model suggests that EBOV antibody reactivity declines over 0.5-2 years after recovery. In a high proportion of healthy survivors, antibody responses undergo rapid restimulation. Vigilant follow-up of survivors and possible elective de novo antigenic stimulation by vaccine immunization should be considered in order to prevent EBOV viral recrudescence in recovering individuals and thereby to mitigate the potential risk of reseeding an outbreak.Limited EBOV outbreaks have been recorded since 1976 1 . The much larger 2013-2016 West African epidemic (28,610 cases) and the ongoing 2018 Eastern Zaire outbreak (3,188 cases as of September 2019) (https://www.who.int/emergencies/diseases/Ebola/drc-2019) in the Democratic Republic of the Congo (DRC) have been more extensive. These larger outbreaks have indicated that the virus can persist in some individuals, with the potential for subsequent viral transmission 2 . Because the number of Ebola outbreaks has been small, we have limited understanding of natural induced immune responses, and our knowledge of vaccine-induced responses comes largely from animal models 3 . These models have indicated that total levels of IgG-binding antibodies can correlate with protection and with neutralizing antibody (nAb) responses, which can typically be low.Outbreaks in humans have provided valuable information regarding therapeutic 4 and vaccine intervention strategies [5][6][7] for EBOV. More recently, nAbs have been the focus of therapeutic development [8][9][10][11][12] . A cocktail of monoclonal antibodies (mAbs) was administered during the 2013-2016 outbreak 12,13 , and trials conducted in the DRC showed evidence of efficacy 14 . In early 2015, two related studies (Ebola-Tx 15 and Ebola-CP 16 ) were established to recruit apparently health survivors of EBOV with the intent of using their convalescent plasma (CP) to treat disease 4,16,17 . We used CP from the donors of the Ebola-CP study (Supplementary Table 1a), in which samples were collected longitudinally (30-500 days) to better ascertain how...

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“…Antibody responses in Ebola survivors also suggest that Ebola RNA identified in post-Ebola syndrome patients may indicate the presence of low levels of persistent viable virus. Adaken et al (2021) found that that levels of neutralizing and total antibodies continue to fluctuate in the plasma of a high proportion of Ebola survivors. The authors contend that this periodic antibody resurgence might follow periods of low-grade Ebola virus replication in body sites/tissues shielded from a full-blown immune response.…”

Pandemic, epidemic, endemic: B cell repertoire analysis reveals unique anti-viral responses to SARS-CoV-2, Ebola and Respiratory Syncytial Virus

“…Another unusual observation was that EBOV survivor's memory B cell populations were more diverse than healthy controls suggesting stimulation with more diverse antigens, or a less structured and directed immune response. A 'decay-stimulation-decay' pattern resulting in the peak of antibody response being some 200 days after infection has previously been reported 67 and cytokine storms during infection may also be contributing to this phenomenon 68,69 . It was not possible to collect blood samples from unrecovered patients, so we do not know if these observations were a requirement of patient recovery or a phenomenon unique to Ebola infection in general.…”

Associations Between Antibody Fc-Mediated Effector Functions and Long-Term Sequelae in Ebola Virus Survivors

“…This increase inflammatory state could be caused by viral persistence, increased susceptibility to other infections, or microbial translocation associated with increased damage to the gut barrier integrity, as observed in chronic HIV patients (38). Continued antigen stimulation after resolution of EBOV disease has been suggested to contribute to sustained CD8 T cell activation (39) and to the periodical waxing and waning of antibody levels (40). Furthermore, high levels of proinflammatory cytokines were associated with lower ADCP, suggesting that inflammation may impair the development or durability of some humoral responses.…”